rs137852296

Variant names:

• chrX-9759390-A-C
• rs137852296
• NM_000273.3:c.397T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-9759390-A-C
• chrX-9759390-A-G
• chrX-9759390-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000273.3(GPR143):​c.397T>G​(p.Trp133Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W133R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98
• Publications: 0 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000273.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-9759390-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10519.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR143	NM_000273.3	c.397T>G	p.Trp133Gly	missense_variant	Exon 3 of 9	ENST00000467482.6	NP_000264.2
GPR143	NM_001440781.1	c.397T>G	p.Trp133Gly	missense_variant	Exon 3 of 9		NP_001427710.1
GPR143	XM_024452388.2	c.145T>G	p.Trp49Gly	missense_variant	Exon 3 of 9		XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR143	ENST00000467482.6	c.397T>G	p.Trp133Gly	missense_variant	Exon 3 of 9	1	NM_000273.3	ENSP00000417161.1
GPR143	ENST00000447366.5	c.145T>G	p.Trp49Gly	missense_variant	Exon 3 of 8	3		ENSP00000390546.2
GPR143	ENST00000431126.1	c.145T>G	p.Trp49Gly	missense_variant	Exon 3 of 6	3		ENSP00000406138.1
GPR143	ENST00000480178.1	n.5T>G		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Trp133 amino acid residue in GPR143. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9529334, 9887374). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with GPR143-related conditions. 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 133 of the GPR143 protein (p.Trp133Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D;.;D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.
PhyloP100		8.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-10	D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.99	D;.;.
Vest4		0.91
MutPred		0.84		Loss of stability (P = 0.0453);.;.;
MVP		0.99
MPC		0.33
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.94
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs137852296; hg19: chrX-9727430;