LYRM4

Summary

LYRM4 (LYR motif containing 4, HGNC:21365) is a protein-coding gene on chromosome 6p25.1, encoding LYR motif-containing protein 4 (Q9HD34). Stabilizing factor, of the core iron-sulfur cluster (ISC) assembly complex, that regulates, in association with NDUFAB1, the stability and the cysteine desulfurase activity of NFS1 and participates in the [2Fe-2S] clusters assembly on the scaffolding protein ISCU. It is a common-essential gene (DepMap: required in 98.2% of cancer cell lines).

The protein encoded by this gene is found in both mitochondria and the nucleus, where it binds cysteine desulfurase and helps free inorganic sulfur for Fe/S clusters. Disruption of this gene negatively impacts mitochondrial and cytosolic iron homeostasis.

Source: NCBI Gene 57128 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation deficiency 19 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 164 total — 2 pathogenic
• Phenotypes (HPO): 28
• Cancer dependency (DepMap): dependent in 98.2% of screened cell lines (common-essential)
• MANE Select transcript: NM_020408

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21365
Approved symbol	LYRM4
Name	LYR motif containing 4
Location	6p25.1
Locus type	gene with protein product
Status	Approved
Aliases	CGI-203, ISD11
Ensembl gene	ENSG00000214113
Ensembl biotype	protein_coding
OMIM	613311
Entrez	57128

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000330636, ENST00000455814, ENST00000458438, ENST00000463032, ENST00000464010, ENST00000468929, ENST00000480566, ENST00000500576, ENST00000606472, ENST00000912483

RefSeq mRNA: 4 — MANE Select: NM_020408 NM_001164840, NM_001164841, NM_001318782, NM_020408

CCDS: CCDS4493, CCDS54961, CCDS54962, CCDS83061

Canonical transcript exons

ENST00000330636 — 3 exons

Exon	Start	End
ENSE00000973364	5216618	5216738
ENSE00001266220	5260648	5260950
ENSE00003702378	5108419	5109491

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 94.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.8285 / max 354.6034, expressed in 1814 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
71535	18.0146	1780
71536	10.8691	1796
203837	0.5117	266
71537	0.3191	168
71538	0.0700	25
71531	0.0221	4
71530	0.0219	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	94.57	gold quality
embryo	UBERON:0000922	90.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.08	gold quality
prefrontal cortex	UBERON:0000451	89.87	gold quality
ganglionic eminence	UBERON:0004023	89.74	gold quality
pituitary gland	UBERON:0000007	89.73	gold quality
adenohypophysis	UBERON:0002196	89.62	gold quality
cortical plate	UBERON:0005343	89.57	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.49	gold quality
spleen	UBERON:0002106	89.41	gold quality
omental fat pad	UBERON:0010414	89.41	gold quality
right adrenal gland	UBERON:0001233	89.40	gold quality
peritoneum	UBERON:0002358	89.39	gold quality
left adrenal gland cortex	UBERON:0035825	89.15	gold quality
left adrenal gland	UBERON:0001234	89.11	gold quality
right adrenal gland cortex	UBERON:0035827	89.07	gold quality
anterior cingulate cortex	UBERON:0009835	89.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.93	gold quality
cingulate cortex	UBERON:0003027	88.92	gold quality
right frontal lobe	UBERON:0002810	88.66	gold quality
adipose tissue	UBERON:0001013	88.65	gold quality
ovary	UBERON:0000992	88.55	gold quality
left ovary	UBERON:0002119	88.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.52	gold quality
adult organism	UBERON:0007023	88.51	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.38	gold quality
connective tissue	UBERON:0002384	88.38	gold quality
adrenal cortex	UBERON:0001235	88.25	gold quality
ventricular zone	UBERON:0003053	88.24	gold quality
heart left ventricle	UBERON:0002084	88.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PITX2

miRNA regulators (miRDB)

44 targeting LYRM4, 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-4283	100.00	66.42	2097
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1284	99.67	73.56	1353
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.2% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 12)

• Frataxin interacts with ISD11 and multiple mitochondrial chaperones. (PMID:17331979)
• ISD11 is important in the biogenesis of Fe-S clusters in mammalian cells. (PMID:19454487)
• LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis. (PMID:21968932)
• Strong candidate gene for mitochondrial disease, based on recessive mutations detected in infantile patients (PMID:22277967)
• Homozygous mutation in LYRM4 was reported in two patients with combined oxidative phosphorylation deficiency. (PMID:23814038)
• Our findings highlight that the ISD11 R68A/R68L mutation display reduced affinity to form a stable subcomplex with NFS1, and thereby fails to prevent NFS1 aggregation resulting in impairment of the Fe-S cluster biogenesis (PMID:26342079)
• Human Isd11 (ISD11) is a helical protein which exists in solution as an equilibrium between monomer, dimeric and tetrameric species when in the absence of human Nfs1 (NFS1). Recombinant ISD11 expressed in E. coli co-purifies with the bacterial orthologue of NFS1, IscS. (PMID:27427956)
• Molecular dynamics flexible fitting of protein structures docked into the EM map of the model revealed a [FXN(42-210)]24.[NFS1]24.[ISD11]24.[ISCU]24 complex, consistent with the measured 1:1:1:1 stoichiometry of its four components. (PMID:27519411)
• The NFS1/ISD11 complex further interacts with scaffold protein ISCU and regulator protein frataxin, thereby forming a quaternary complex for Fe-S cluster formation. (PMID:28271877)
• analysis of the NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters (PMID:28634302)
• The molecular structure of the human mitochondrial cysteine desulfurase complex consisting of two copies each of NFS1, ISD11, and acyl carrier protein has been described. (PMID:29983374)
• In this work, the structure of the human mitochondrial ACP-ISD11 heterodimer was determined at 2.0 A resolution. (PMID:31664822)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lyrm4	ENSDARG00000078352
danio_rerio	LYRM4	ENSDARG00000101110
mus_musculus	Lyrm4	ENSMUSG00000046573
rattus_norvegicus	Lyrm4	ENSRNOG00000047970

Paralogs (1): SDHAF1 (ENSG00000205138)

Protein

Protein identifiers

LYR motif-containing protein 4 — Q9HD34 (reviewed: Q9HD34)

All UniProt accessions (6): C9J799, C9JRX8, C9JY28, F5H189, H7C4Q5, Q9HD34

UniProt curated annotations — full annotation on UniProt →

Function. Stabilizing factor, of the core iron-sulfur cluster (ISC) assembly complex, that regulates, in association with NDUFAB1, the stability and the cysteine desulfurase activity of NFS1 and participates in the [2Fe-2S] clusters assembly on the scaffolding protein ISCU. The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5. May also participates in the iron-sulfur protein biogenesis in the cytoplasm through its interaction with the cytoplasmic form of NFS1.

Subunit / interactions. Homodimer. Component of the mitochondrial core iron-sulfur cluster (ISC) complex composed of NFS1, LYRM4, NDUFAB1, ISCU, FXN, and FDX2; this complex is a heterohexamer containing two copies of each monomer. Component of the cyteine desulfurase complex composed of NFS1, LYRM4 and NDUFAB1; this complex contributes to the stability and cysteine desulfurase activity of NFS1. Interacts with FXN; this interaction is nickel-dependent. Forms a complex with the cytoplasmic form of NFS1; this complex increases the stability and cysteine desulfurase activity of NFS1. Interacts with NFS1. Component of a complex composed of FXN, NFS1, LYRM4 and ISCU.

Subcellular location. Mitochondrion. Nucleus.

Tissue specificity. Reduced mRNA levels in Friedreich ataxia patients.

Disease relevance. Combined oxidative phosphorylation deficiency 19 (COXPD19) [MIM:615595] A mitochondrial disorder characterized by respiratory distress, hypotonia, and severe lactic acidosis in the newborn period. Other features include gastroesophageal reflux and elevated liver enzymes with normal synthetic function. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Cofactor biosynthesis; iron-sulfur cluster biosynthesis.

Similarity. Belongs to the complex I LYR family.

RefSeq proteins (4): NP_001158312, NP_001158313, NP_001305711, NP_065141* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008011	Complex1_LYR_dom	Domain
IPR045297	Complex1_LYR_LYRM4	Domain
IPR051522	ISC_assembly_LYR	Family

Pfam: PF05347

UniProt features (11 total): helix 4, binding site 2, sequence variant 2, chain 1, modified residue 1, turn 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
6UXE	X-RAY DIFFRACTION	1.57
6W1D	X-RAY DIFFRACTION	1.79
6WIH	X-RAY DIFFRACTION	1.9
6WI2	X-RAY DIFFRACTION	1.95
6ODD	X-RAY DIFFRACTION	2
8TVT	X-RAY DIFFRACTION	2
8RMC	ELECTRON MICROSCOPY	2.26
8RMF	ELECTRON MICROSCOPY	2.33
8RMG	ELECTRON MICROSCOPY	2.46
8PK8	ELECTRON MICROSCOPY	2.49
8RME	ELECTRON MICROSCOPY	2.49
7RTK	X-RAY DIFFRACTION	2.5
8RMD	ELECTRON MICROSCOPY	2.52
8PK9	ELECTRON MICROSCOPY	2.58
5WGB	X-RAY DIFFRACTION	2.75
8PKA	ELECTRON MICROSCOPY	2.75
5USR	X-RAY DIFFRACTION	3.09
5WKP	X-RAY DIFFRACTION	3.15
6NZU	ELECTRON MICROSCOPY	3.2
5WLW	X-RAY DIFFRACTION	3.32

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HD34-F1	93.57	0.88

Functional residue map

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

Ligand- & substrate-binding residues (2): 6; 44

Post-translational modifications (1): 47

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1362409	Mitochondrial iron-sulfur cluster biogenesis
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle
R-HSA-9865881	Complex III assembly
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-611105	Respiratory electron transport
R-HSA-71403	Citric acid cycle (TCA cycle)

MSigDB gene sets: 183 (showing top): chr6p25, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, TIEN_INTESTINE_PROBIOTICS_24HR_UP, GOCC_TRANSFERASE_COMPLEX, GOCC_NUCLEAR_BODY, GOCC_MITOCHONDRIAL_MATRIX, MARSON_BOUND_BY_FOXP3_STIMULATED, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GOCC_MITOCHONDRIAL_PROTEIN_CONTAINING_COMPLEX, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY, GOMF_STRUCTURAL_MOLECULE_ACTIVITY, GOBP_2FE_2S_CLUSTER_ASSEMBLY, ONKEN_UVEAL_MELANOMA_DN, REACTOME_MITOCHONDRIAL_IRON_SULFUR_CLUSTER_BIOGENESIS

GO Biological Process (3): iron-sulfur cluster assembly (GO:0016226), [2Fe-2S] cluster assembly (GO:0044571), [4Fe-4S] cluster assembly (GO:0044572)

GO Molecular Function (4): structural molecule activity (GO:0005198), protein homodimerization activity (GO:0042803), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), nuclear body (GO:0016604), mitochondrial [2Fe-2S] assembly complex (GO:0099128), L-cysteine desulfurase complex (GO:1990221), iron-sulfur cluster assembly complex (GO:1990229)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Metabolism	2
Aerobic respiration and respiratory electron transport	2
Citric acid cycle (TCA cycle)	1
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
iron-sulfur cluster assembly	2
molecular_function	2
binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
metallo-sulfur cluster assembly	1
identical protein binding	1
protein dimerization activity	1
mitochondrion	1
intracellular organelle lumen	1
nucleoplasm	1
intracellular membraneless organelle	1
mitochondrial protein-containing complex	1
L-cysteine desulfurase complex	1
iron-sulfur cluster assembly complex	1
sulfurtransferase complex	1
protein-containing complex	1

Protein interactions and networks

STRING

2330 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LYRM4	ISCU	Q9H1K1	999
LYRM4	NFS1	Q9Y697	999
LYRM4	FXN	Q16595	999
LYRM4	HSPA9	P30036	912
LYRM4	FDX2	Q6P4F2	888
LYRM4	ACO1	P21399	879
LYRM4	NDUFAB1	O14561	844
LYRM4	ACO2	Q99798	838
LYRM4	IBA57	Q5T440	811
LYRM4	NFU1	Q9UMS0	811
LYRM4	ISCA1	Q9BUE6	810
LYRM4	ISCA2	Q86U28	806
LYRM4	HSCB	Q8IWL3	768
LYRM4	FDXR	P22570	766
LYRM4	CIAO3	Q9H6Q4	745

IntAct

38 interactions, top by confidence:

A	B	Type	Score
ZWINT	NDC80	psi-mi:“MI:0914”(association)	0.940
LYRM4	NFS1	psi-mi:“MI:0407”(direct interaction)	0.770
LYRM4	NFS1	psi-mi:“MI:0915”(physical association)	0.770
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
GPX7	GAK	psi-mi:“MI:0914”(association)	0.640
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
ISCU	acpP	psi-mi:“MI:0915”(physical association)	0.570
acpP	ISCU	psi-mi:“MI:0915”(physical association)	0.570
HLA-DPB1	IDE	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
NDUFAB1	GLDC	psi-mi:“MI:0914”(association)	0.530
acpP	FXN	psi-mi:“MI:0915”(physical association)	0.490
LYRM4	NECTIN2	psi-mi:“MI:0915”(physical association)	0.370
Pcgf1	SCAMP3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
NDUFAB1	SDHB	psi-mi:“MI:0914”(association)	0.350
CHCHD1	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
KEAP1	ASNS	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CARTPT	MEIS1	psi-mi:“MI:0914”(association)	0.350
LYRM4	UBA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (101): LYRM4 (Affinity Capture-MS), LYRM4 (Affinity Capture-MS), LYRM4 (Affinity Capture-MS), LYRM4 (Affinity Capture-MS), NFS1 (Co-fractionation), LYRM4 (Affinity Capture-MS), ISCU (Affinity Capture-MS), LYRM4 (Affinity Capture-MS), FXN (Affinity Capture-MS), NFS1 (Affinity Capture-MS), IDE (Affinity Capture-MS), NRD1 (Affinity Capture-MS), CHCHD2 (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCB (Affinity Capture-MS)

ESM2 similar proteins: A0JPA6, A1C9A5, A1D9R4, A2R2Q4, A3LNG8, A4DA73, A5DH70, A5PLG0, A9UL63, B0YEJ3, B4F7A1, B5FZA8, B5X5U9, B5XD90, B6GWX1, B8JLQ0, B8MP27, C4Y4R9, C5DEI4, C9SBR9, O46098, P56556, P82116, Q02366, Q0CVW0, Q0MQA3, Q0MQA4, Q0MQA5, Q0P574, Q0UIG9, Q0VCG0, Q2M2S9, Q4QQY2, Q4SQJ2, Q4WHK3, Q5AX36, Q5BBH7, Q5REC3, Q5U5X0, Q5XIY4

Diamond homologs: B5FZA8, B5X5U9, B5XD90, B8JLQ0, O46098, O60068, P82116, Q0VCG0, Q54FN9, Q6DCS1, Q6Q560, Q8K215, Q9HD34, Q8IEK7, A3KNJ8, B5FXA0, B5XCZ6, Q0VCR0, Q503U1, Q54PT6, Q6IPR1, Q91V16, Q9VJG4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
LYRM4	“form complex”	“Mitochondrial Fe-S Cluster Assembly Complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 38 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
iron-sulfur cluster assembly	5	88.5×	4e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	121
Likely benign	19
Benign	17

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
102450	NM_020408.6(LYRM4):c.203G>T (p.Arg68Leu)	Pathogenic
3062881	GRCh37/hg19 6p25.1(chr6:5172636-5200031)x1	Pathogenic

SpliceAI

2313 predictions. Top by Δscore:

Variant	Effect	Δscore
6:5216141:TTAC:T	donor_gain	1.0000
6:5216371:A:AC	donor_gain	1.0000
6:5216372:C:CC	donor_gain	1.0000
6:5216375:A:AC	donor_gain	1.0000
6:5216376:A:C	donor_gain	1.0000
6:5216612:TCTTA:T	donor_loss	1.0000
6:5216613:CTTA:C	donor_loss	1.0000
6:5216614:TTAC:T	donor_loss	1.0000
6:5216615:TACCT:T	donor_loss	1.0000
6:5216616:A:AG	donor_loss	1.0000
6:5216734:ATGTT:A	acceptor_gain	1.0000
6:5216735:TGTT:T	acceptor_gain	1.0000
6:5216737:TT:T	acceptor_gain	1.0000
6:5216738:TCTAA:T	acceptor_loss	1.0000
6:5216739:C:CC	acceptor_gain	1.0000
6:5216739:C:T	acceptor_loss	1.0000
6:5216740:T:A	acceptor_loss	1.0000
6:5216743:A:AC	acceptor_gain	1.0000
6:5216750:C:CT	acceptor_gain	1.0000
6:5216751:A:T	acceptor_gain	1.0000
6:5110329:T:TA	donor_gain	0.9900
6:5110406:C:CT	donor_gain	0.9900
6:5110407:T:TT	donor_gain	0.9900
6:5115287:T:A	donor_gain	0.9900
6:5216140:TTTA:T	donor_gain	0.9900
6:5216616:A:AC	donor_gain	0.9900
6:5216617:C:CC	donor_gain	0.9900
6:5216617:CCTGT:C	donor_gain	0.9900
6:5216736:GTT:G	acceptor_gain	0.9900
6:5216743:A:C	acceptor_gain	0.9900

AlphaMissense

587 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:5216705:G:C	F40L	0.993
6:5216705:G:T	F40L	0.993
6:5216707:A:G	F40L	0.993
6:5216650:C:G	A59P	0.988
6:5216706:A:G	F40S	0.981
6:5216710:C:G	A39P	0.980
6:5216730:G:T	A32D	0.977
6:5260674:G:C	S20R	0.977
6:5260674:G:T	S20R	0.977
6:5260676:T:G	S20R	0.977
6:5216622:C:G	R68P	0.974
6:5216718:A:T	I36K	0.973
6:5216649:G:T	A59D	0.972
6:5260648:C:A	R29I	0.971
6:5216731:C:G	A32P	0.965
6:5216718:A:C	I36R	0.961
6:5216618:C:A	Q69H	0.958
6:5216618:C:G	Q69H	0.958
6:5260648:C:G	R29T	0.956
6:5260665:G:C	F23L	0.956
6:5260665:G:T	F23L	0.956
6:5260667:A:G	F23L	0.956
6:5260684:A:G	L17P	0.956
6:5216707:A:T	F40I	0.955
6:5216706:A:C	F40C	0.950
6:5260666:A:G	F23S	0.947
6:5216738:T:A	R29S	0.944
6:5216738:T:G	R29S	0.944
6:5216628:A:G	I66T	0.942
6:5216720:C:A	R35S	0.941

dbSNP variants (sampled 300 via entrez): RS1000005692 (6:5040193 C>T), RS1000021678 (6:5150500 G>A,C), RS1000036855 (6:5246354 G>C,T), RS1000040795 (6:5087750 G>A), RS1000042191 (6:5242792 A>C,G), RS1000044633 (6:5107422 C>G,T), RS1000044889 (6:5164589 CA>C,CAA), RS1000062446 (6:5190386 A>G), RS1000076893 (6:5205267 G>A), RS1000078273 (6:5040914 C>T), RS1000102902 (6:5199373 G>C,T), RS1000113569 (6:5086536 T>C), RS1000128671 (6:5067364 C>T), RS1000157480 (6:5050617 C>A), RS1000163456 (6:5120435 G>A,C)

Disease associations

OMIM: gene MIM:613311 | disease phenotypes: MIM:615595

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 19	Moderate	Autosomal recessive
severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency	Supportive	Autosomal recessive

Mondo (2): combined oxidative phosphorylation deficiency 19 (MONDO:0014269), (MONDO:0018337)

Orphanet (1): Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency (Orphanet:397593)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001252	Hypotonia
HP:0001319	Neonatal hypotonia
HP:0001403	Macrovesicular hepatic steatosis
HP:0001414	Microvesicular hepatic steatosis
HP:0001508	Failure to thrive
HP:0001612	Weak cry
HP:0001942	Metabolic acidosis
HP:0001946	Ketosis
HP:0002020	Gastroesophageal reflux
HP:0002033	Poor suck
HP:0002098	Respiratory distress
HP:0002240	Hepatomegaly
HP:0002395	Lower limb hyperreflexia
HP:0002421	Poor head control
HP:0002490	Increased CSF lactate
HP:0003128	Lactic acidosis
HP:0003557	Increased variability in muscle fiber diameter
HP:0003623	Neonatal onset
HP:0003648	Lacticaciduria
HP:0010307	Stridor
HP:0011968	Feeding difficulties
HP:0012707	Elevated brain lactate level by MRS
HP:0030774	Mitochondrial swelling
HP:0030948	Elevated gamma-glutamyltransferase level
HP:0031956	Elevated circulating aspartate aminotransferase concentration
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0032988	Persistent head lag

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001263_8	Height	3.000000e-06
GCST008142_2	Systolic blood pressure	8.000000e-06
GCST90002404_240	Red cell distribution width	3.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, affects expression, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
bisphenol A	decreases methylation	1
sodium arsenite	increases abundance, increases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	increases methylation	1
Arsenic	increases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	affects cotreatment, affects expression	1
Methyl Methanesulfonate	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	increases expression	1
Zinc	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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