X-9725831-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000273.3(GPR143):c.1130C>T(p.Ala377Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000906 in 110,323 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000091 (0 hom., 1 hem., cov: 21)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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]

TBL1X (HGNC:11585): (transducin beta like 1 X-linked) The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This encoded protein is found as a subunit in corepressor SMRT (silencing mediator for retinoid and thyroid receptors) complex along with histone deacetylase 3 protein. This gene is located adjacent to the ocular albinism gene and it is thought to be involved in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype. Four transcript variants encoding two different isoforms have been found for this gene. This gene is highly similar to the Y chromosome TBL1Y gene. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3279342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR143	NM_000273.3	c.1130C>T	p.Ala377Val	missense_variant	9/9	ENST00000467482.6
GPR143	XM_024452388.2	c.878C>T	p.Ala293Val	missense_variant	9/9
GPR143	XM_005274541.4	c.*105C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR143	ENST00000467482.6	c.1130C>T	p.Ala377Val	missense_variant	9/9	1	NM_000273.3	P1
TBL1X	ENST00000647060.1	c.1554+10828G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00000906 AC: 1 AN: 110323 Hom.: 0 Cov.: 21 AF XY: 0.0000307 AC XY: 1 AN XY: 32557

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000906 AC: 1 AN: 110323 Hom.: 0 Cov.: 21 AF XY: 0.0000307 AC XY: 1 AN XY: 32557

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

This variant is not present in population databases (gnomAD no frequency). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with GPR143-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 377 of the GPR143 protein (p.Ala377Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.33	T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.67	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.63
Sift	Benign	0.081	T
Sift4G	Uncertain	0.018	D
Polyphen		0.21	B
Vest4		0.15
MutPred		0.47		Gain of relative solvent accessibility (P = 0.1894);
MVP		0.97
MPC		0.047
ClinPred		0.34	T
GERP RS		2.4
Varity_R		0.10
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1359127369; hg19: chrX-9693871;