rs62635018

Variant names:

• chrX-9765714-C-A
• rs62635018
• NM_000273.3:c.104G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-9765714-C-A
• chrX-9765714-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000273.3(GPR143):​c.104G>T​(p.Gly35Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000399 in 1,003,693 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G35D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000040 (0 hom. 1 hem.)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20
• 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: Likely_pathogenic. The variant received 6 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-9765714-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10521.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR143	NM_000273.3	c.104G>T	p.Gly35Val	missense_variant	Exon 1 of 9	ENST00000467482.6	NP_000264.2
GPR143	NM_001440781.1	c.104G>T	p.Gly35Val	missense_variant	Exon 1 of 9		NP_001427710.1
GPR143	XM_024452388.2	c.-2-4888G>T		intron_variant	Intron 1 of 8		XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR143	ENST00000467482.6	c.104G>T	p.Gly35Val	missense_variant	Exon 1 of 9	1	NM_000273.3	ENSP00000417161.1
GPR143	ENST00000447366.5	c.-2-4888G>T		intron_variant	Intron 1 of 7	3		ENSP00000390546.2
GPR143	ENST00000431126.1	c.-3+406G>T		intron_variant	Intron 1 of 5	3		ENSP00000406138.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000399 AC: 4 AN: 1003693 Hom.: 0 Cov.: 30 AF XY: 0.00000309 AC XY: 1 AN XY: 323699

African (AFR) AF: 0.00 AC: 0 AN: 21382

American (AMR) AF: 0.00 AC: 0 AN: 23943

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17340

East Asian (EAS) AF: 0.00 AC: 0 AN: 22631

South Asian (SAS) AF: 0.00 AC: 0 AN: 46280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25743

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2981

European-Non Finnish (NFE) AF: 0.00000499 AC: 4 AN: 801021

Other (OTH) AF: 0.00 AC: 0 AN: 42372

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 30, 2023

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. 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 not 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 glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 35 of the GPR143 protein (p.Gly35Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.38	N
REVEL	Pathogenic	0.66
Sift	Benign	0.99	T
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.81		Loss of disorder (P = 0.0449);
MVP		0.92
MPC		0.31
ClinPred		0.93	D
GERP RS		4.5
PromoterAI		-0.0014	Neutral
Varity_R		0.26
gMVP		0.70
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs62635018; hg19: chrX-9733754;