ERF

Summary

ERF (ETS2 repressor factor, HGNC:3444) is a protein-coding gene on chromosome 19q13.2, encoding ETS domain-containing transcription factor ERF (P50548). Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter.

ETS2 is a transcription factor and protooncogene involved in development, apoptosis, and the regulation of telomerase. The protein encoded by this gene binds to the ETS2 promoter and is a strong repressor of ETS2 transcription. Several transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 2077 — RefSeq curated summary.

At a glance

• Gene–disease (curated): craniosynostosis 4 (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 302 total — 29 pathogenic, 21 likely-pathogenic
• MANE Select transcript: NM_006494

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3444
Approved symbol	ERF
Name	ETS2 repressor factor
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	PE-2, PE2
Ensembl gene	ENSG00000105722
Ensembl biotype	protein_coding
OMIM	611888
Entrez	2077

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000222329, ENST00000440177, ENST00000593944, ENST00000595448, ENST00000595941, ENST00000596818, ENST00000598965, ENST00000715593, ENST00000925766

RefSeq mRNA: 4 — MANE Select: NM_006494 NM_001301035, NM_001308402, NM_001312656, NM_006494

CCDS: CCDS12600, CCDS77308

Canonical transcript exons

ENST00000222329 — 4 exons

Exon	Start	End
ENSE00000847276	42254978	42255128
ENSE00003459226	42250331	42250565
ENSE00004027330	42247569	42249738
ENSE00004027331	42249827	42249942

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 97.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.1328 / max 59.3413, expressed in 1674 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181164	31.1914	1802
181165	1.5497	1029
181163	1.3699	863
181158	0.8263	477
181159	0.8198	538
181161	0.6623	348
181160	0.4871	263
181162	0.4177	223

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.15	gold quality
mucosa of stomach	UBERON:0001199	96.93	gold quality
gall bladder	UBERON:0002110	96.41	gold quality
left uterine tube	UBERON:0001303	96.17	gold quality
ventricular zone	UBERON:0003053	96.10	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.48	gold quality
adenohypophysis	UBERON:0002196	95.01	gold quality
body of uterus	UBERON:0009853	94.46	gold quality
nerve	UBERON:0001021	94.13	gold quality
tibial nerve	UBERON:0001323	94.13	gold quality
right ovary	UBERON:0002118	93.92	gold quality
sural nerve	UBERON:0015488	93.58	gold quality
left ovary	UBERON:0002119	93.47	gold quality
metanephros cortex	UBERON:0010533	93.29	gold quality
right lobe of liver	UBERON:0001114	93.16	gold quality
omental fat pad	UBERON:0010414	93.12	gold quality
left lobe of thyroid gland	UBERON:0001120	93.11	gold quality
peritoneum	UBERON:0002358	93.05	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.02	gold quality
endocervix	UBERON:0000458	92.95	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.93	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.92	gold quality
apex of heart	UBERON:0002098	92.91	gold quality
tibial artery	UBERON:0007610	92.90	gold quality
popliteal artery	UBERON:0002250	92.88	gold quality
pituitary gland	UBERON:0000007	92.71	gold quality
right atrium auricular region	UBERON:0006631	92.69	gold quality
right lung	UBERON:0002167	92.68	gold quality
aorta	UBERON:0000947	92.54	gold quality
ascending aorta	UBERON:0001496	92.51	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.11
E-MTAB-6058	no	8.58

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA0760.1	ERF	Ets-related
MA0760.2	ERF	Ets-related
MA1934.1	ERF::FIGLA	Ets-related::Tal-related
MA1934.2	ERF::FIGLA	Ets-related::Tal-related
MA1935.1	ERF::FOXI1	Ets-related::FOX
MA1935.2	ERF::FOXI1	Ets-related::FOX
MA1936.1	ERF::FOXO1	Ets-related::FOX
MA1936.2	ERF::FOXO1	Ets-related::FOX
MA1937.1	ERF::HOXB13	Ets-related::HOX-related factors
MA1937.2	ERF::HOXB13	Ets-related::HOX-related factors
MA1938.1	ERF::NHLH1	Ets-related::Tal-related
MA1938.2	ERF::NHLH1	Ets-related::Tal-related
MA1939.1	ERF::SREBF2	Ets-related::bHLH-ZIP
MA1939.2	ERF::SREBF2	Ets-related::bHLH-ZIP

JASPAR matrix evidence (PMIDs): PMID:20517297, PMID:31913281, PMID:24218641, PMID:9488464, PMID:23050235

miRNA regulators (miRDB)

105 targeting ERF, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-124-3P	99.89	73.74	3043

Literature-anchored findings (GeneRIF, showing 22)

• Ets-2 Repressor Factor (ERF) physically interacts with the cytomegalovirus major immediate-early promoter (MIEP) and represses MIEP activity in undifferentiated non-permissive T2 embryonal carcinoma cells (PMID:12533699)
• a complex interplay between Ets/Id family members and c-Myc that may be an important determinant of the diversity of telomerase activity in leukemia and other cancers (PMID:14611815)
• Chromosome 21 transcription factor Ets2, overexpressed in Down syndrome, is expressed in neurons. Overexpression causes increased apoptosis of neurons from Ets2 transgenic mice and also involves activation of caspase-3. (PMID:14678752)
• Differential repression of c-myc and cdc2 gene expression by ERF and PE-1/METS. (PMID:17525531)
• Erf provides a direct link between the RAS/ERK signaling and the transcriptional regulation of c-Myc and suggests that RAS/ERK attenuation actively regulates cell fate (PMID:17699159)
• Data demonstrate that induction of EGR1 involves ERK-mediated down-regulation of microRNA-191 and phosphorylation of the ETS2 repressor factor (ERF) repressor, which subsequently leaves the nucleus. (PMID:22198386)
• This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes (PMID:23354439)
• ERF-related craniosynostosis should be suspected in patients presenting with multiple suture or sagittal synostosis (PMID:26097063)
• We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p.Tyr89Cys substitution in ERF. (PMID:27738187)
• Systematic genomic sequencing of prostate cancer in African-American men revealed new insights into prostate cancer, including the identification of ERF as a prostate cancer gene; somatic copy-number alteration differences; and uncommon PIK3CA and PTEN alterations. This study highlights the importance of inclusion of underrepresented minorities in cancer sequencing studies. (PMID:28515055)
• data provide evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF and they raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors (PMID:28614298)
• Identification of novel prostate cancer drivers, ERF, CREB3L1, and POU2F2, using RegNetDriver, a framework for integration of genetic and epigenetic alterations with tissue-specific regulatory network. (PMID:28750683)
• Mutation in the ERF gene is associated with craniosynostosis syndrome. (PMID:30758909)
• Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). (PMID:32370745)
• Variable pulmonary manifestations in Chitayat syndrome: Six additional affected individuals. (PMID:32592542)
• Identification and analysis of micro-exons in AP2/ERF and MADS gene families. (PMID:32986930)
• Dissection of contiguous gene effects for deletions around ERF on chromosome 19. (PMID:33993607)
• Deletion of ERF and CIC causes abnormal skull morphology and global developmental delay. (PMID:34117072)
• Cognitive, Behavioural, Speech, Language and Developmental Outcomes Associated with Pathogenic Variants in the ERF Gene. (PMID:35761471)
• The CIC-ERF co-deletion underlies fusion-independent activation of ETS family member, ETV1, to drive prostate cancer progression. (PMID:36383412)
• Activation of gamma-globin expression by LncRNA-mediated ERF promoter hypermethylation in beta-thalassemia. (PMID:38218889)
• Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis. (PMID:38824261)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	erfl3	ENSDARG00000062801
danio_rerio	erf	ENSDARG00000063417
mus_musculus	Erf	ENSMUSG00000040857
rattus_norvegicus	Erf	ENSRNOG00000020426

Paralogs (28): ETV1 (ENSG00000006468), ETV7 (ENSG00000010030), SPI1 (ENSG00000066336), ELF4 (ENSG00000102034), ETV2 (ENSG00000105672), ELF2 (ENSG00000109381), ELK3 (ENSG00000111145), ETV3 (ENSG00000117036), ELF1 (ENSG00000120690), SPDEF (ENSG00000124664), ELK1 (ENSG00000126767), ETS1 (ENSG00000134954), EHF (ENSG00000135373), ELF5 (ENSG00000135374), ETV6 (ENSG00000139083), FLI1 (ENSG00000151702), GABPA (ENSG00000154727), ERG (ENSG00000157554), ETS2 (ENSG00000157557), ELK4 (ENSG00000158711), ELF3 (ENSG00000163435), FEV (ENSG00000163497), SPIC (ENSG00000166211), ETV4 (ENSG00000175832), ETV5 (ENSG00000244405), ETV3L (ENSG00000253831), ERFL (ENSG00000268041), SPIB (ENSG00000269404)

Protein

Protein identifiers

ETS domain-containing transcription factor ERF — P50548 (reviewed: P50548)

Alternative names: Ets2 repressor factor, PE-2

All UniProt accessions (4): P50548, A0AAQ5BII5, M0QX79, M0QXN0

UniProt curated annotations — full annotation on UniProt →

Function. Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter. May regulate other genes involved in cellular proliferation. Required for extraembryonic ectoderm differentiation, ectoplacental cone cavity closure, and chorioallantoic attachment. May be important for regulating trophoblast stem cell differentiation.

Subcellular location. Nucleus.

Tissue specificity. Highest levels in testis, ovary, pancreas, and heart.

Post-translational modifications. Phosphorylated by multiple kinases including MAPK1/ERK2 at THR-526. Phosphorylation regulates the activity of ERF.

Disease relevance. Craniosynostosis 4 (CRS4) [MIM:600775] A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. The disease is caused by variants affecting the gene represented in this entry. Chitayat syndrome (CHYTS) [MIM:617180] An autosomal dominant syndrome characterized by hyperphalangism, partial syndactyly, bilateral accessory phalanx resulting in shortened index fingers, hallux valgus, brachydactyly, facial anomalies, diffuse bronchomalacia, and respiratory distress at birth and in infancy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ETS family.

Isoforms (2)

UniProt ID	Names	Canonical?
P50548-1	1	yes
P50548-2	2

RefSeq proteins (4): NP_001287964, NP_001295331, NP_001299585, NP_006485* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000418	Ets_dom	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR046328	ETS_fam	Family

Pfam: PF00178

UniProt features (50 total): modified residue 15, compositionally biased region 6, region of interest 5, strand 5, sequence variant 4, helix 4, cross-link 3, sequence conflict 2, turn 2, chain 1, DNA-binding region 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7JSA	X-RAY DIFFRACTION	2.85
7JSL	X-RAY DIFFRACTION	4.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50548-F1	55.46	0.16

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (18): 3, 7, 20, 24, 185, 190, 327, 431, 435, 441, 444, 526, 531, 532, 548, 465, 481, 512

Mutagenesis-validated functional residues (1):

Position	Phenotype
526	loss of a phosphorylation site.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2559585	Oncogene Induced Senescence

MSigDB gene sets: 463 (showing top): RNGTGGGC_UNKNOWN, FXR_IR1_Q6, E2F_Q4_01, YAATNRNNNYNATT_UNKNOWN, MYOGENIN_Q6, BROWNE_HCMV_INFECTION_8HR_UP, GCANCTGNY_MYOD_Q6, CREBP1_Q2, AP2_Q3, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, CREB_Q4, KOYAMA_SEMA3B_TARGETS_UP, DOANE_RESPONSE_TO_ANDROGEN_DN, ATF1_Q6

GO Biological Process (4): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), cell differentiation (GO:0030154), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular Senescence	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
negative regulation of DNA-templated transcription	1
cellular developmental process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

830 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERF	FURIN	P09958	516
ERF	PRSS57	Q6UWY2	507
ERF	CCNB1	P14635	504
ERF	SH2D3A	Q9BRG2	479
ERF	GATA1	P15976	470
ERF	EPHA8	P29322	447
ERF	MAPK3	P27361	428
ERF	PFDN6	O15212	413
ERF	CREB1	P16220	404
ERF	SH2D3C	Q8N5H7	400
ERF	OR2Z1	Q8NG97	373
ERF	PNMA6E	A0A0J9YXQ4	370
ERF	SP5	Q6BEB4	366
ERF	SRC	P12931	359
ERF	MAPK1	P28482	354

IntAct

145 interactions, top by confidence:

A	B	Type	Score
TUBGCP5	TUBG1	psi-mi:“MI:0914”(association)	0.840
DCAF7	DIAPH1	psi-mi:“MI:0914”(association)	0.730
WRAP53	TCP1	psi-mi:“MI:0914”(association)	0.690
MAPK1	DHPS	psi-mi:“MI:0914”(association)	0.640
ERF	ZRANB1	psi-mi:“MI:0915”(physical association)	0.560
ERF	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
ERF	MCRS1	psi-mi:“MI:0915”(physical association)	0.560
ERF	TLE5	psi-mi:“MI:0915”(physical association)	0.560
ANTXR1	POTEF	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
SDF4	GTPBP6	psi-mi:“MI:0914”(association)	0.530
AOC3	AOC2	psi-mi:“MI:0914”(association)	0.530
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
C1QTNF9B	PLOD3	psi-mi:“MI:0914”(association)	0.530
ERF	TBL1X	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
ERF	XPOT	psi-mi:“MI:0915”(physical association)	0.400
ETV4	ERF	psi-mi:“MI:0915”(physical association)	0.400
CSNK1A1	ERF	psi-mi:“MI:0915”(physical association)	0.400
	ERF	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (140): ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), ERF (Affinity Capture-MS), SPOP (Affinity Capture-Western), ERF (Reconstituted Complex)

ESM2 similar proteins: A0A1W2PQ73, A1YF16, A1YG93, A2RU54, A5PKG8, O02786, O14813, O15353, O35602, O43638, O57601, P13297, P19419, P28360, P35548, P41969, P42580, P43687, P49640, P50223, P50548, P52946, P52950, P63156, P63157, P70459, P78413, Q03358, Q14549, Q2VL78, Q2VL79, Q2VL82, Q2VL83, Q2VL84, Q2VL85, Q2VL86, Q2VL87, Q2VL88, Q5NSW5, Q61575

Diamond homologs: A0A1W2PQ73, A0JN51, A1A4L6, A1YF15, A1YG61, A1YG91, A2D4Z7, A2T737, A2T762, A3FEM2, A4GTP4, A8WFJ9, O00321, O01519, O70132, O70273, O95238, P01105, P10157, P11308, P11536, P13474, P14921, P15036, P15037, P15062, P18755, P18756, P19102, P19419, P20105, P26323, P27577, P28322, P28324, P29773, P29774, P29775, P29776, P32519

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CyclinB/CDK1	down-regulates	ERF	phosphorylation
CDK1	down-regulates	ERF	phosphorylation
MAPK1	down-regulates	ERF	phosphorylation
MAPK1	up-regulates	ERF	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

302 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	21
Uncertain significance	157
Likely benign	56
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064659	NC_000019.10:g.42227530_42259211del	Pathogenic
1070490	NC_000019.9:g.(?_42759120)_42759196del	Pathogenic
1502851	NM_006494.4(ERF):c.911_913del (p.Ser304del)	Pathogenic
2122554	NM_006494.4(ERF):c.272dup (p.Arg92fs)	Pathogenic
2133130	NM_006494.4(ERF):c.1021del (p.Gln341fs)	Pathogenic
218956	NM_006494.4(ERF):c.23-2A>G	Pathogenic
218957	NM_006494.4(ERF):c.1A>G (p.Met1Val)	Pathogenic
267443	NM_006494.4(ERF):c.266A>G (p.Tyr89Cys)	Pathogenic
2683998	NM_006494.4(ERF):c.11del (p.Pro4fs)	Pathogenic
2683999	NM_006494.4(ERF):c.136dup (p.Ile46fs)	Pathogenic
2684000	NM_006494.4(ERF):c.1509del (p.Phe504fs)	Pathogenic
2810553	NM_006494.4(ERF):c.997_1034del (p.Leu332_His333insTer)	Pathogenic
3339269	NM_006494.4(ERF):c.506C>A (p.Ser169Ter)	Pathogenic
3654560	NM_006494.4(ERF):c.856dup (p.Met286fs)	Pathogenic
3686735	NM_006494.4(ERF):c.253del (p.Leu85fs)	Pathogenic
4082546	NM_006494.4(ERF):c.103G>T (p.Glu35Ter)	Pathogenic
4250662	NM_006494.4(ERF):c.65del (p.Pro22fs)	Pathogenic
4618797	NM_006494.4(ERF):c.679dup (p.His227fs)	Pathogenic
4715860	NM_006494.4(ERF):c.121G>T (p.Glu41Ter)	Pathogenic
476627	NM_006494.4(ERF):c.619C>T (p.Arg207Ter)	Pathogenic
476628	NM_006494.4(ERF):c.733del (p.Leu245fs)	Pathogenic
520696	NM_006494.4(ERF):c.785del (p.Pro262fs)	Pathogenic
543070	NM_006494.4(ERF):c.566_567del (p.Asp188_Cys189insTer)	Pathogenic
55923	NM_006494.4(ERF):c.547C>T (p.Arg183Ter)	Pathogenic
55927	NM_006494.4(ERF):c.1270C>T (p.Gln424Ter)	Pathogenic
582072	NM_006494.4(ERF):c.223C>T (p.Gln75Ter)	Pathogenic
583126	NM_006494.4(ERF):c.-44_22+11del	Pathogenic
936483	NM_006494.4(ERF):c.144G>A (p.Trp48Ter)	Pathogenic
985387	NM_006494.4(ERF):c.697C>T (p.Arg233Ter)	Pathogenic
1018043	NM_006494.4(ERF):c.110T>C (p.Leu37Pro)	Likely pathogenic

SpliceAI

1044 predictions. Top by Δscore:

Variant	Effect	Δscore
19:42249735:CCCC:C	acceptor_gain	1.0000
19:42249736:CCCC:C	acceptor_gain	1.0000
19:42249819:GTACT:G	donor_loss	1.0000
19:42249821:ACT:A	donor_loss	1.0000
19:42249823:TCACC:T	donor_loss	1.0000
19:42249824:CAC:C	donor_loss	1.0000
19:42249825:A:AT	donor_loss	1.0000
19:42249826:C:T	donor_loss	1.0000
19:42249939:ATAG:A	acceptor_gain	1.0000
19:42249940:TAG:T	acceptor_gain	1.0000
19:42249940:TAGCT:T	acceptor_loss	1.0000
19:42249941:AGCTG:A	acceptor_loss	1.0000
19:42249943:C:CC	acceptor_gain	1.0000
19:42249943:CTGTG:C	acceptor_loss	1.0000
19:42250347:G:C	donor_gain	1.0000
19:42249591:G:T	acceptor_gain	0.9900
19:42249736:CCC:C	acceptor_gain	0.9900
19:42249737:CC:C	acceptor_gain	0.9900
19:42249737:CCC:C	acceptor_gain	0.9900
19:42249738:CC:C	acceptor_gain	0.9900
19:42249739:C:CA	acceptor_loss	0.9900
19:42249740:T:A	acceptor_loss	0.9900
19:42249818:GGTAC:G	donor_loss	0.9900
19:42249820:TAC:T	donor_loss	0.9900
19:42249825:A:AC	donor_gain	0.9900
19:42249825:ACCAG:A	donor_gain	0.9900
19:42249826:C:CC	donor_gain	0.9900
19:42249826:CCAGC:C	donor_gain	0.9900
19:42249938:AATAG:A	acceptor_gain	0.9900
19:42249939:ATAGC:A	acceptor_loss	0.9900

AlphaMissense

3481 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:42249871:T:A	K110I	1.000
19:42249876:G:C	F108L	1.000
19:42249876:G:T	F108L	1.000
19:42249877:A:G	F108S	1.000
19:42249878:A:G	F108L	1.000
19:42249879:A:C	N107K	1.000
19:42249879:A:T	N107K	1.000
19:42249882:G:C	F106L	1.000
19:42249882:G:T	F106L	1.000
19:42249883:A:C	F106C	1.000
19:42249883:A:G	F106S	1.000
19:42249884:A:C	F106V	1.000
19:42249884:A:G	F106L	1.000
19:42249884:A:T	F106I	1.000
19:42249885:C:A	K105N	1.000
19:42249885:C:G	K105N	1.000
19:42249887:T:C	K105E	1.000
19:42249889:T:C	Y104C	1.000
19:42249890:A:C	Y104D	1.000
19:42249890:A:G	Y104H	1.000
19:42249890:A:T	Y104N	1.000
19:42249894:G:C	F102L	1.000
19:42249894:G:T	F102L	1.000
19:42249895:A:C	F102C	1.000
19:42249895:A:G	F102S	1.000
19:42249896:A:C	F102V	1.000
19:42249896:A:G	F102L	1.000
19:42249896:A:T	F102I	1.000
19:42249899:G:A	R101W	1.000
19:42249900:T:A	K100N	1.000

dbSNP variants (sampled 300 via entrez): RS1001092823 (19:42254522 G>A,C), RS1001213075 (19:42252060 T>A,C), RS1001244355 (19:42253464 T>TA), RS1001307657 (19:42256794 G>A), RS1001424019 (19:42253446 C>A,T), RS1001579449 (19:42252378 G>A,C,T), RS1002133671 (19:42250842 G>C), RS1002344638 (19:42255252 C>G,T), RS1002362141 (19:42255371 C>T), RS1003356733 (19:42248119 T>C), RS1003363153 (19:42250136 G>A,C), RS1003440334 (19:42251268 A>C,G), RS1003450357 (19:42247831 G>A), RS1003479923 (19:42254433 G>A), RS1003571623 (19:42254261 T>TC)

Disease associations

OMIM: gene MIM:611888 | disease phenotypes: MIM:123100, MIM:617180, MIM:163950, MIM:600775, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
craniosynostosis 4	Definitive	Autosomal dominant
Chitayat syndrome	Definitive	Autosomal dominant
Noonan syndrome	Strong	Autosomal dominant
Crouzon syndrome	Supportive	Autosomal dominant
isolated scaphocephaly	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
craniosynostosis 4	Definitive	AD

Mondo (10): TWIST1-related craniosynostosis (MONDO:0007399), Chitayat syndrome (MONDO:0014956), Noonan syndrome (MONDO:0018997), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), craniosynostosis 4 (MONDO:0010929), neurodevelopmental disorder (MONDO:0700092), craniosynostosis (MONDO:0015469), plasma cell myeloma (MONDO:0009693), Crouzon syndrome (MONDO:0007405), (MONDO:0018112)

Orphanet (6): OBSOLETE: Isolated oxycephaly (Orphanet:63440), Noonan syndrome (Orphanet:648), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), Craniosynostosis (Orphanet:1531), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003394	Craniofacial Dysostosis	C05.116.099.370.231; C05.660.207.231; C16.131.621.207.231
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D065886	Neurodevelopmental Disorders	F03.625
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression, affects expression	4
Tretinoin	affects expression, decreases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
coumarin	increases phosphorylation	1
caffeic acid	increases expression, increases reaction	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	increases expression	1
(+)-JQ1 compound	decreases expression	1
MT19c compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression	1
Caffeine	decreases phosphorylation	1
Doxorubicin	decreases expression	1
Drugs, Chinese Herbal	increases expression, increases reaction	1
Hydrogen Peroxide	affects cotreatment, increases expression	1
Ozone	affects expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 2 embryonic stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2WM	Abcam HEK293T ERF KO	Transformed cell line	Female
CVCL_YN08	WAe001-A-33	Embryonic stem cell	Male
CVCL_YN09	WAe001-A-34	Embryonic stem cell	Male

Clinical trials (associated diseases)

297 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05474924	PHASE4	UNKNOWN	The Role of Budesonide Intrapolyp Injection in CRSwNP
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00104104	PHASE4	COMPLETED	A Multiple Myeloma Trial in Patients With Bone Metastases
NCT00211211	PHASE4	COMPLETED	FREE Study - Fracture Reduction Evaluation
NCT00242528	PHASE4	WITHDRAWN	Open-label Study, to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Bone Lesions Secondary to Multiple Myeloma.
NCT00257114	PHASE4	COMPLETED	Evaluation of VELCADE Given as Retreatment to Multiple Myeloma Patients for Efficacy, Safety and Tolerability
NCT00352703	PHASE4	COMPLETED	PROMPT - Palifermin in Reduction of Oral Mucositis in PBSC Transplantation
NCT00361140	PHASE4	COMPLETED	Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
NCT00622505	PHASE4	COMPLETED	Zoledronic Acid Treatment (Every 4 or 12 Weeks) to Prevent Skeletal Complications in Advanced Multiple Myeloma Participants
NCT00652041	PHASE4	COMPLETED	Bortezomib/Adriamycine/Melfalan/Prednisone (VAMP)/Thalidomide/Cyclophosphamide/Dexamethasone (TaCyDex) or Bortezomib/Melfalan/Prednisone (V-MP)/TaCyDex) in Refractary or Relapsed Multiple Myeloma
NCT00733538	PHASE4	COMPLETED	Stage I Multiple Myeloma Treatment
NCT01087008	PHASE4	COMPLETED	Zoledronic Acid in Patients With Multiple Myeloma and Asymptomatic Biochemical Relapse
NCT01249690	PHASE4	UNKNOWN	Efficacy Study of PAD and TAD in Newly Diagnosed Multiple Myeloma
NCT01410929	PHASE4	WITHDRAWN	Evaluation of Vertebral Compression Fracture Fixation With RF Kyphoplasty in Patients With Multiple Myeloma
NCT01731886	PHASE4	COMPLETED	Lenalidomide and Dexamethasone With/Without Stem Cell Transplant in Patients With Multiple Myeloma
NCT01868828	PHASE4	UNKNOWN	A Study of PAD Versus Velcade, Cyclophosphamide and Dexamethasone (VCD) Treatment in Subjects With Multiple Myeloma
NCT02268890	PHASE4	COMPLETED	A Pharmacokinetic Study of Bortezomib in Taiwanese Participants With Multiple Myeloma
NCT02286830	PHASE4	COMPLETED	Prolonged Protection From Bone Disease in Multiple Myeloma
NCT02559154	PHASE4	UNKNOWN	Modified Bortezomib-based Combination Therapy for Multiple Myeloma
NCT02577783	PHASE4	UNKNOWN	PDD vs PAD to Treat Initially Diagnosed MM
NCT02773550	PHASE4	TERMINATED	Treatment With a Scheme With Low Doses of Bortezomib / Melphalan / Prednisone (MPV) in Patients With Multiple Myeloma
NCT02958969	PHASE4	COMPLETED	Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma
NCT03173092	PHASE4	TERMINATED	A Study of Ixazomib (NINLARO®) in Combination With Lenalidomide and Dexamethasone (IRD) for the Treatment of Participants With Multiple Myeloma (MM)
NCT03619252	PHASE4	COMPLETED	Pneumococcal Vaccination of Multiple Myeloma Patients on Novel Agents
NCT03768960	PHASE4	COMPLETED	A Study of DARZALEX (Daratumumab) In Indian Participants With Relapsed and Refractory Multiple Myeloma, Whose Prior Therapy Included a Proteasome Inhibitor and an Immunomodulatory Agent
NCT03829371	PHASE4	ACTIVE_NOT_RECRUITING	STUDY COMPARING TWO STANDARD TREATMENTS IN AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE POPULATION AFFECTED BY MULTIPLE MYELOMA
NCT03908138	PHASE4	UNKNOWN	RDD Versus VDD in Newly Diagnosed Patients With Multiple Myeloma
NCT04217967	PHASE4	COMPLETED	Ixazomib, Lenalidomide, and Combination for Maintenance in NDMM Patients
NCT04952766	PHASE4	COMPLETED	Study Evaluating SARS-CoV-2 (COVID-19) Humoral Response After BNT162b2 Vaccine in Immunocompromised Adults Compared to Healthy Adults
NCT04989140	PHASE4	UNKNOWN	Study of Pomalidomide, Oral Dexamethasone and Ixazomib in Patients With Relapsed MM Who Have Received Lenalidomide
NCT05183139	PHASE4	WITHDRAWN	A Multicenter In-class Transition Study of Ixazomib Combined With Pomalidomide and Dexamethasone or With Lenalidomide and Dexamethasone in Adults With Relapsed/Refractory Multiple Myeloma
NCT05201781	PHASE4	RECRUITING	A Long-term Study for Participants Previously Treated With Ciltacabtagene Autoleucel
NCT05429515	PHASE4	NOT_YET_RECRUITING	Effect of HFR-SUPRA in the Treatment of Multiple Myeloma-related Acute Kidney Injury
NCT05511428	PHASE4	COMPLETED	Home Based Daratumumab Administration for Patients With Multiple Myeloma
NCT05545202	PHASE4	UNKNOWN	A Randomized, Comparative, Double-blind Trial of Pentaisomaltose and Dimethyl Sulphoxide for Cryoprotection of Hematopoietic Stem Cells in Subjects With Multiple Myeloma or Malignant Lymphoma With a Need for Autologous Transplantation
NCT05555329	PHASE4	COMPLETED	Alternative Dosing Scheme of Pomalidomide 4 mg Every Other Day Versus Pomalidomide 2 mg and 4 mg Every Day; the POMAlternative Study