NM_000273.3:c.874T>G

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 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, single submitter P:2 O:1
• Conservation: PhyloP100: 7.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 chrnull-null-null-null is described in UniProt as null.
• 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 id is 98647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-9741349-A-C is described in Lovd as [Likely_pathogenic]. Variant chrX-9741349-A-C is described in Lovd as [Pathogenic].

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	XM_005274541.4	c.874T>G	p.Trp292Gly	missense_variant	Exon 7 of 9		XP_005274598.1
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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000516

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

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). -

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Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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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

- -

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;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-11	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.93		Loss of helix (P = 0.0444);.;
MVP		1.0
MPC		0.35
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs62635045; hg19: chrX-9709389;