chrX-9741349-A-C

Variant names:

• chrX-9741349-A-C
• rs62635045
• NM_000273.3:c.874T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000273.3(GPR143):​c.874T>G​(p.Trp292Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000371 in 808,031 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W292C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.92
• Publications: 3 publications found

Genes affected

GPR143 (HGNC:20145): (G protein-coupled receptor 143) This gene encodes a protein that binds to heterotrimeric G proteins and is targeted to melanosomes in pigment cells. This protein is thought to be involved in intracellular signal transduction mechanisms. Mutations in this gene cause ocular albinism type 1, also referred to as Nettleship-Falls type ocular albinism, a severe visual disorder. A related pseudogene has been identified on chromosome Y. [provided by RefSeq, Dec 2009]

GPR143 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• ocular albinism

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• nystagmus 6, congenital, X-linked

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• X-linked recessive ocular albinism

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-9741347-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 98649.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-9741349-A-C is Pathogenic according to our data. Variant chrX-9741349-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 98647.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR143	NM_000273.3	c.874T>G	p.Trp292Gly	missense_variant	Exon 7 of 9	ENST00000467482.6	NP_000264.2
GPR143	NM_001440781.1	c.874T>G	p.Trp292Gly	missense_variant	Exon 7 of 9		NP_001427710.1
GPR143	XM_024452388.2	c.622T>G	p.Trp208Gly	missense_variant	Exon 7 of 9		XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR143	ENST00000467482.6	c.874T>G	p.Trp292Gly	missense_variant	Exon 7 of 9	1	NM_000273.3	ENSP00000417161.1
GPR143	ENST00000447366.5	c.622T>G	p.Trp208Gly	missense_variant	Exon 7 of 8	3		ENSP00000390546.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000371 AC: 3 AN: 808031 Hom.: 0 Cov.: 13 AF XY: 0.00000443 AC XY: 1 AN XY: 225887

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20987

American (AMR) AF: 0.00 AC: 0 AN: 33504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17307

East Asian (EAS) AF: 0.00 AC: 0 AN: 28623

South Asian (SAS) AF: 0.00 AC: 0 AN: 47056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39705

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2956

European-Non Finnish (NFE) AF: 0.00000516 AC: 3 AN: 581674

Other (OTH) AF: 0.00 AC: 0 AN: 36219

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Mar 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp292 amino acid residue in GPR143. Other variant(s) that disrupt this residue have been observed in individuals with GPR143-related conditions (PMID: 11214907, 26785811), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GPR143 function (PMID: 11115845). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GPR143 protein function. ClinVar contains an entry for this variant (Variation ID: 98647). This missense change has been observed in individuals with GPR143-related conditions (PMID: 8634705, 28041643, 32581362). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 292 of the GPR143 protein (p.Trp292Gly).

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Albinism Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

GPR143-related foveal hypoplasia Pathogenic:1

May 08, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 2 heterozygote(s), 0 homozygote(s), 1 hemizygote(s)) ; This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with ocular albinism (PMIDs: 32830442, 28041643, 8634705). It has been reported in one 14 year old boy with nystagmus, low vision, foveal hypoplasia and ocular hypopigmentation (PMID: 26785811). It has also been reported as pathogenic by a clinical laboratory in ClinVar. - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs transfected into COS7 cells resulted in defective glycosylation and protein retention in the ER (PMID: 11115845). In addition, PC12 cells harbouring the mutant construct failed to inhibit neurite outgrowth compared to the WT (PMID: 31606330); Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The alternative change to a cystine has also been reported as likely pathogenic in ClinVar and also in an individual with ocular albinism (PMID: 11214907); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from tryptophan to glycine; This variant is heterozygous; This gene is associated with X-linked recessive disease; No published segregation evidence has been identified for this variant; Variant is not located in an established domain, motif, hotspot or informative constraint region; Loss of function is a known mechanism of disease in this gene and is associated with GPR143-related foveal hypoplasia (MONDO:0700230).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-11	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.98
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.98
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62635045; hg19: chrX-9709389;