SHF

Summary

SHF (Src homology 2 domain containing F, HGNC:25116) is a protein-coding gene on chromosome 15q21.1, encoding SH2 domain-containing adapter protein F (Q7M4L6). Adapter protein which may play a role in the regulation of apoptosis in response to PDGF.

Predicted to enable phosphotyrosine residue binding activity. Predicted to be involved in apoptotic process.

Source: NCBI Gene 90525 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 48 total
• MANE Select transcript: NM_001394037

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25116
Approved symbol	SHF
Name	Src homology 2 domain containing F
Location	15q21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000138606
Ensembl biotype	protein_coding
OMIM	617313
Entrez	90525

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000290894, ENST00000458022, ENST00000558294, ENST00000558685, ENST00000559566, ENST00000560471, ENST00000560540, ENST00000560734, ENST00000561091, ENST00000561239, ENST00000561278, ENST00000690270

RefSeq mRNA: 16 — MANE Select: NM_001394037 NM_001301168, NM_001301169, NM_001301170, NM_001301171, NM_001394037, NM_001394038, NM_001394039, NM_001394040, NM_001394041, NM_001394042, NM_001394043, NM_001394044, NM_001394045, NM_001394046, NM_001394047, NM_138356

CCDS: CCDS10120, CCDS73721, CCDS76749, CCDS76750, CCDS91993, CCDS91994

Canonical transcript exons

ENST00000690270 — 7 exons

Exon	Start	End
ENSE00000931268	45172147	45172318
ENSE00001277951	45173576	45173716
ENSE00003483091	45175219	45175425
ENSE00003622820	45178165	45178306
ENSE00003629262	45171883	45172002
ENSE00003641710	45167214	45168133
ENSE00003936520	45187454	45187966

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 98.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3790 / max 562.9347, expressed in 1327 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149688	7.1783	1064
149691	0.8574	512
149687	0.2362	99
149686	0.1071	52

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	98.14	gold quality
cerebellar cortex	UBERON:0002129	98.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.06	gold quality
cerebellum	UBERON:0002037	96.91	gold quality
cortical plate	UBERON:0005343	96.27	gold quality
ganglionic eminence	UBERON:0004023	95.61	gold quality
right lobe of liver	UBERON:0001114	91.53	gold quality
ventricular zone	UBERON:0003053	88.03	gold quality
left ovary	UBERON:0002119	86.65	gold quality
right frontal lobe	UBERON:0002810	86.59	gold quality
right ovary	UBERON:0002118	86.24	gold quality
prefrontal cortex	UBERON:0000451	85.73	gold quality
nucleus accumbens	UBERON:0001882	85.37	gold quality
anterior cingulate cortex	UBERON:0009835	85.28	gold quality
upper arm skin	UBERON:0004263	84.55	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.33	gold quality
hypothalamus	UBERON:0001898	84.17	gold quality
amygdala	UBERON:0001876	83.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	83.04	gold quality
descending thoracic aorta	UBERON:0002345	83.01	gold quality
body of uterus	UBERON:0009853	82.90	gold quality
ovary	UBERON:0000992	82.82	gold quality
mucosa of stomach	UBERON:0001199	82.68	gold quality
liver	UBERON:0002107	82.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.52	gold quality
thoracic aorta	UBERON:0001515	82.51	gold quality
neocortex	UBERON:0001950	82.48	gold quality
ascending aorta	UBERON:0001496	82.47	gold quality
right adrenal gland cortex	UBERON:0035827	82.37	gold quality
left adrenal gland cortex	UBERON:0035825	82.28	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting SHF, 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-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-4464	98.95	67.73	820
HSA-MIR-4748	98.95	67.53	810
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-665	97.60	65.64	1781

Literature-anchored findings (GeneRIF, showing 3)

• Patients showing high ALK and low Shf mRNA expressions showed poor prognosis. (PMID:23360421)
• SHF Acts as a Novel Tumor Suppressor in Glioblastoma Multiforme by Disrupting STAT3 Dimerization. (PMID:35843865)
• SHF confers radioresistance in colorectal cancer by the regulation of mitochondrial DNA copy number. (PMID:36527512)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Shf	ENSMUSG00000033256
rattus_norvegicus	Shf	ENSRNOG00000028685

Paralogs (3): SHD (ENSG00000105251), SHB (ENSG00000107338), SHE (ENSG00000169291)

Protein

Protein identifiers

SH2 domain-containing adapter protein F — Q7M4L6 (reviewed: Q7M4L6)

All UniProt accessions (11): A0A8I5QJ71, Q7M4L6, F8W6V4, H0YKA8, H0YLD8, H0YLM1, H0YLW6, H0YMN4, H0YN16, H0YNF2, H0YNJ2

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein which may play a role in the regulation of apoptosis in response to PDGF.

Subunit / interactions. Interacts with phosphorylated ‘Tyr-720’ of PDGFRA via its SH2 domain.

Tissue specificity. Expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine and colon.

Post-translational modifications. May become phosphorylated upon binding to PDGFRA.

Miscellaneous. The sequence described in PubMed:11095946 is over-extended by 57 aa at the N-terminus due to the presence of an uncorrected 5’ mismatch compared to the reference genome sequence.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7M4L6-1	1	yes
Q7M4L6-2	2

RefSeq proteins (15): NP_001288097, NP_001288098, NP_001288099, NP_001288100, NP_001380966, NP_001380967, NP_001380968, NP_001380969, NP_001380970, NP_001380971, NP_001380972, NP_001380974, NP_001380975, NP_001380976, NP_612365 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR035044	SHF_SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR051846	SH2_domain_adapters	Family

Pfam: PF00017

UniProt features (10 total): region of interest 3, sequence conflict 2, chain 1, domain 1, compositionally biased region 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7M4L6-F1	63.25	0.20

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 (1): 201

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 102 (showing top): SRF_Q5_01, TCF4_Q5, HNF4_DR1_Q3, HNF4_01, PPAR_DR1_Q2, SANSOM_APC_TARGETS_UP, LEF1_Q6, EGR1_01, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOMF_PHOSPHOPROTEIN_BINDING, ZF5_01, GOMF_PROTEIN_PHOSPHORYLATED_AMINO_ACID_BINDING, HNF4ALPHA_Q6, ER_Q6_01, PID_PDGFRA_PATHWAY

GO Biological Process (2): apoptotic process (GO:0006915), signal transduction (GO:0007165)

GO Molecular Function (1): phosphotyrosine residue binding (GO:0001784)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein phosphorylated amino acid binding	1

Protein interactions and networks

STRING

200 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHF	SERPINF2	P08697	577
SHF	IREB2	P48200	478
SHF	ALK	Q9UM73	465
SHF	SH2D6	Q7Z4S9	376
SHF	RIMOC1	A6NDU8	366
SHF	PRKRIP1	Q9H875	354
SHF	TRIR	Q9BQ61	342
SHF	FAM151A	Q8WW52	314
SHF	SHC1	P29353	311
SHF	G5EA03	G5EA03	282
SHF	RAB43	Q86YS6	274
SHF	TADA1	Q96BN2	269
SHF	SETD1A	O15047	267
SHF	ST8SIA2	Q92186	266
SHF	ADSL	P30566	259

IntAct

3 interactions, top by confidence:

A	B	Type	Score
ALK	SHF	psi-mi:“MI:0915”(physical association)	0.370
SHF	Stat5b	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): PDGFRA (Reconstituted Complex), SHF (Synthetic Lethality), SHF (Two-hybrid), SHF (Affinity Capture-MS)

ESM2 similar proteins: A2A7Y5, A6NKC9, B1ASB6, F1MGG3, M3WHG5, O54824, O88834, P15391, P24394, P25917, P25918, P27987, P60669, Q13796, Q14005, Q32PJ7, Q3LRP3, Q49AM3, Q4R2Z8, Q5FVQ5, Q5JXC2, Q6VYH9, Q6ZMY3, Q7M4L6, Q7Z591, Q7Z6P3, Q80VR2, Q80VW7, Q863Z5, Q8BG26, Q8BI17, Q8BLR5, Q8BZW2, Q8C886, Q8CB87, Q8IY92, Q8NAV2, Q8NDX1, Q8NHY3, Q8R2H3

Diamond homologs: A6QLK6, A8XI74, F1RDG9, O35413, O43639, O45539, O55033, O55043, O75791, O89032, O94868, P00519, P00520, P00521, P00522, P00523, P00525, P00526, P00528, P05480, P06239, P07948, P08487, P08631, P09760, P10447, P10686, P10936, P12931, P13115, P13116, P14084, P14085, P15054, P16333, P16591, P17713, P19174, P25020, P25911

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1383 predictions. Top by Δscore:

Variant	Effect	Δscore
15:45168132:TCC:T	acceptor_loss	1.0000
15:45168134:C:CC	acceptor_gain	1.0000
15:45168134:CTGG:C	acceptor_loss	1.0000
15:45168135:T:A	acceptor_loss	1.0000
15:45171878:CTCA:C	donor_gain	1.0000
15:45171879:TCA:T	donor_loss	1.0000
15:45171880:CACT:C	donor_loss	1.0000
15:45171881:A:AC	donor_gain	1.0000
15:45171881:AC:A	donor_loss	1.0000
15:45171882:C:CT	donor_gain	1.0000
15:45171882:CTTGA:C	donor_gain	1.0000
15:45171999:CCAG:C	acceptor_gain	1.0000
15:45172000:CAGC:C	acceptor_gain	1.0000
15:45172001:AG:A	acceptor_gain	1.0000
15:45172002:GCTAA:G	acceptor_loss	1.0000
15:45172003:C:CC	acceptor_gain	1.0000
15:45172003:C:T	acceptor_loss	1.0000
15:45172009:A:AC	acceptor_gain	1.0000
15:45172009:A:C	acceptor_gain	1.0000
15:45172145:A:AC	donor_gain	1.0000
15:45172146:C:CC	donor_gain	1.0000
15:45172146:CA:C	donor_gain	1.0000
15:45175214:CTCA:C	donor_loss	1.0000
15:45175215:TCACC:T	donor_loss	1.0000
15:45175216:CA:C	donor_loss	1.0000
15:45175218:C:A	donor_loss	1.0000
15:45175435:C:CT	acceptor_gain	1.0000
15:45175441:A:T	acceptor_gain	1.0000
15:45178160:CTCA:C	donor_loss	1.0000
15:45178161:TCAC:T	donor_loss	1.0000

AlphaMissense

3123 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:45167969:G:T	P417H	1.000
15:45167978:A:C	L414R	1.000
15:45167978:A:G	L414P	1.000
15:45167978:A:T	L414Q	1.000
15:45167993:G:T	A409D	1.000
15:45167994:C:G	A409P	1.000
15:45167997:C:G	G408R	1.000
15:45167997:C:T	G408R	1.000
15:45168002:A:T	I406N	1.000
15:45168008:A:G	L404P	1.000
15:45168008:A:T	L404Q	1.000
15:45168024:A:C	Y399D	1.000
15:45168041:G:T	P393H	1.000
15:45168044:A:T	V392D	1.000
15:45168052:G:C	F389L	1.000
15:45168052:G:T	F389L	1.000
15:45168053:A:G	F389S	1.000
15:45168054:A:G	F389L	1.000
15:45168054:A:T	F389I	1.000
15:45168061:G:C	S386R	1.000
15:45168061:G:T	S386R	1.000
15:45168063:T:G	S386R	1.000
15:45168071:C:A	G383V	1.000
15:45168072:C:G	G383R	1.000
15:45168074:A:G	L382P	1.000
15:45168074:A:T	L382Q	1.000
15:45168104:A:G	L372P	1.000
15:45168110:A:C	M370R	1.000
15:45168110:A:G	M370T	1.000
15:45168110:A:T	M370K	1.000

dbSNP variants (sampled 300 via entrez): RS1000086737 (15:45189769 T>C), RS1000323140 (15:45170444 T>A,C), RS1000454346 (15:45196878 G>A), RS1000455294 (15:45177431 T>G), RS1000574303 (15:45195299 T>G), RS1000679452 (15:45200607 A>C), RS1000707259 (15:45200497 A>T), RS1000757884 (15:45170011 G>T), RS1000894319 (15:45190644 G>A), RS1000941381 (15:45190303 GATAA>G), RS1000943142 (15:45170554 T>C), RS1000961627 (15:45182184 G>A), RS1001012119 (15:45194874 G>A), RS1001061848 (15:45177028 C>G), RS1001090151 (15:45188635 C>G)

Disease associations

OMIM: gene MIM:617313 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006633_31	Initial alcohol sensitivity	2.000000e-06
GCST008097_5	Bisphosphonate-associated atypical femoral fracture	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009958	response to bisphosphonate
EFO:0009960	atypical femoral fracture

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects response to substance, decreases expression, affects methylation	2
sotorasib	affects cotreatment, increases expression	1
dimethylselenide	increases expression, increases oxidation	1
CGP 52608	affects binding, increases reaction	1
trametinib	increases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Ozone	increases abundance, affects expression	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	decreases methylation	1
Reactive Oxygen Species	increases oxidation, increases expression	1
Lithium Chloride	decreases expression	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	increases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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