rs58933950

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000273.3(GPR143):​c.455G>A​(p.Ser152Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.7e-7 ( 0 hom. 1 hem. )
Failed GnomAD Quality Control

Consequence

GPR143
NM_000273.3 missense, splice_region

Scores

5
8
4
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 6.79
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GPR143NM_000273.3 linkc.455G>A p.Ser152Asn missense_variant, splice_region_variant Exon 3 of 9 ENST00000467482.6 NP_000264.2 P51810
GPR143XM_005274541.4 linkc.455G>A p.Ser152Asn missense_variant, splice_region_variant Exon 3 of 9 XP_005274598.1
GPR143XM_024452388.2 linkc.203G>A p.Ser68Asn missense_variant, splice_region_variant Exon 3 of 9 XP_024308156.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GPR143ENST00000467482.6 linkc.455G>A p.Ser152Asn missense_variant, splice_region_variant Exon 3 of 9 1 NM_000273.3 ENSP00000417161.1 P51810
GPR143ENST00000447366.5 linkc.203G>A p.Ser68Asn missense_variant, splice_region_variant Exon 3 of 8 3 ENSP00000390546.2 H7BZN6
GPR143ENST00000431126.1 linkc.203G>A p.Ser68Asn missense_variant, splice_region_variant Exon 3 of 6 3 ENSP00000406138.1 C9J9N1
GPR143ENST00000480178.1 linkn.63G>A splice_region_variant, non_coding_transcript_exon_variant Exon 1 of 3 2

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
9.66e-7
AC:
1
AN:
1035692
Hom.:
0
Cov.:
22
AF XY:
0.00000316
AC XY:
1
AN XY:
316546
show subpopulations
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:
0.00000127
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ocular albinism, type I Pathogenic:1Uncertain:1
Apr 01, 1998
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 25, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Other:1
-
Retina International
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
D;.;D
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.77
T;T;T
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.81
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.5
M;.;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.5
N;.;N
REVEL
Pathogenic
0.69
Sift
Benign
0.077
T;.;D
Sift4G
Uncertain
0.016
D;D;.
Polyphen
0.97
D;.;.
Vest4
0.87
MutPred
0.72
Gain of relative solvent accessibility (P = 0.0215);.;.;
MVP
0.90
MPC
0.065
ClinPred
0.97
D
GERP RS
4.7
Varity_R
0.40
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.78
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.78
Position offset: 0

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.

Other links and lift over

dbSNP: rs58933950; hg19: chrX-9727372; API