X-9746132-G-C

Variant names:

• chrX-9746132-G-C
• rs61733440
• NM_000273.3:c.570C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000273.3(GPR143):​c.570C>G​(p.His190Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,840 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 (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0680

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a topological_domain Extracellular (size 20) in uniprot entity GP143_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000273.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR143	NM_000273.3	c.570C>G	p.His190Gln	missense_variant	Exon 5 of 9	ENST00000467482.6	NP_000264.2
GPR143	XM_005274541.4	c.570C>G	p.His190Gln	missense_variant	Exon 5 of 9		XP_005274598.1
GPR143	XM_024452388.2	c.318C>G	p.His106Gln	missense_variant	Exon 5 of 9		XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR143	ENST00000467482.6	c.570C>G	p.His190Gln	missense_variant	Exon 5 of 9	1	NM_000273.3	ENSP00000417161.1
GPR143	ENST00000447366.5	c.318C>G	p.His106Gln	missense_variant	Exon 5 of 8	3		ENSP00000390546.2
GPR143	ENST00000431126.1	c.318C>G	p.His106Gln	missense_variant	Exon 5 of 6	3		ENSP00000406138.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111840 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34002

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000954

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111840 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34002

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000954

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 190 of the GPR143 protein (p.His190Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GPR143-related conditions. ClinVar contains an entry for this variant (Variation ID: 1355604). 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 with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	8.9
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.95	D;.;D
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.84	T;T;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	D;.;D
REVEL	Pathogenic	0.66
Sift	Benign	0.034	D;.;T
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.81
MutPred		0.81		Gain of helix (P = 0.062);.;.;
MVP		0.94
MPC		0.20
ClinPred		0.98	D
GERP RS		-6.7
Varity_R		0.47
gMVP		0.71

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: rs61733440; hg19: chrX-9714172;