Genetic Variant GPR143:p.Gly35Asp (chrX-9765714-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000273.3(GPR143):c.104G>A(p.Gly35Asp) variant causes a missense change. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G35V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

GPR143
NM_000273.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 4.20

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

inherited retinal dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
ocular albinism
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
nystagmus 6, congenital, X-linked
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
X-linked recessive ocular albinism
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

GPR143 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

PP5

Variant X-9765714-C-T is Pathogenic according to our data. Variant chrX-9765714-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10521.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000273.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR143	NM_000273.3	MANE Select	c.104G>A	p.Gly35Asp	missense	Exon 1 of 9	NP_000264.2
	GPR143	NM_001440781.1		c.104G>A	p.Gly35Asp	missense	Exon 1 of 9	NP_001427710.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPR143	ENST00000467482.6	TSL:1 MANE Select	c.104G>A	p.Gly35Asp	missense	Exon 1 of 9	ENSP00000417161.1
GPR143	ENST00000447366.5	TSL:3	c.-2-4888G>A		intron	N/A	ENSP00000390546.2
GPR143	ENST00000431126.1	TSL:3	c.-3+406G>A		intron	N/A	ENSP00000406138.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1003691

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

323697

African (AFR)

AF:

0.00

AC:

AN:

21382

American (AMR)

AF:

0.00

AC:

AN:

23943

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17340

East Asian (EAS)

AF:

0.00

AC:

AN:

22631

South Asian (SAS)

AF:

0.00

AC:

AN:

46277

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25743

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2981

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

801022

Other (OTH)

AF:

0.00

AC:

AN:

42372

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Ocular albinism, type I

Pathogenic:1

Nov 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.63

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

PhyloP100

4.2

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.84

Sift

Benign

0.098

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.93

MutPred

0.77

Gain of relative solvent accessibility (P = 0.0023)

MVP

1.0

MPC

0.31

ClinPred

0.96

GERP RS

4.5

PromoterAI

-0.053

Neutral

(source)

Varity_R

0.42

gMVP

0.86

Mutation Taster

=41/59

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over