rs1057520200

Positions:

• chrX-9765816-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000273.3(GPR143):​c.2T>C​(p.Met1?) variant causes a start lost 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPR143 NM_000273.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.23

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 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-9765816-A-G is Pathogenic according to our data. Variant chrX-9765816-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 377335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-9765816-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR143	NM_000273.3	c.2T>C	p.Met1?	start_lost	1/9	ENST00000467482.6	NP_000264.2
GPR143	XM_005274541.4	c.2T>C	p.Met1?	start_lost	1/9		XP_005274598.1
GPR143	XM_024452388.2	c.-2-4990T>C		intron_variant			XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR143	ENST00000467482.6	c.2T>C	p.Met1?	start_lost	1/9	1	NM_000273.3	ENSP00000417161.1
GPR143	ENST00000447366.5	c.-2-4990T>C		intron_variant		3		ENSP00000390546.2
GPR143	ENST00000431126.1	c.-3+304T>C		intron_variant		3		ENSP00000406138.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 993827 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 312275

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 02, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GPR143 protein in which other variant(s) (p.Gly84Asp) have been determined to be pathogenic (PMID: 8634705, 11115845, 12868035, 31574285). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 377335). Disruption of the initiator codon has been observed in individual(s) with ocular albinism (PMID: 31106028). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GPR143 mRNA. The next in-frame methionine is located at codon 85. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.80
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.66		Gain of glycosylation at M1 (P = 0.0058);
MVP		0.99
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.92
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1057520200; hg19: chrX-9733856;