Variant X-9746132-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0680

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein
GPR143	NM_000273.3 linkuse as main transcript	c.570C>G	p.His190Gln	missense_variant	5/9	ENST00000467482.6	NP_000264.2
GPR143	XM_005274541.4 linkuse as main transcript	c.570C>G	p.His190Gln	missense_variant	5/9		XP_005274598.1
GPR143	XM_024452388.2 linkuse as main transcript	c.318C>G	p.His106Gln	missense_variant	5/9		XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GPR143	ENST00000467482.6 linkuse as main transcript	c.570C>G	p.His190Gln	missense_variant	5/9	1	NM_000273.3	ENSP00000417161	P1
GPR143	ENST00000447366.5 linkuse as main transcript	c.318C>G	p.His106Gln	missense_variant	5/8	3		ENSP00000390546
GPR143	ENST00000431126.1 linkuse as main transcript	c.318C>G	p.His106Gln	missense_variant	5/6	3		ENSP00000406138

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111840

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34002

show subpopulations

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.:

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111840

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34002

show subpopulations

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

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 22, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with GPR143-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with glutamine at codon 190 of the GPR143 protein (p.His190Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

8.9

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.95

D;.;D

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.84

T;T;D

M_CAP

Uncertain

0.092

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.67

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over