dbSNP rs137852298: GPR143:p.Ser89Phe (chrX-9760811-G-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000273.3(GPR143):c.266C>T(p.Ser89Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 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).

Frequency

Genomes: not found (cov: 22)

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:1

Conservation

PhyloP100: 8.55

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000273.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant X-9760811-G-A is Pathogenic according to our data. Variant chrX-9760811-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10522.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GPR143	NM_000273.3 link	c.266C>T	p.Ser89Phe	missense_variant	Exon 2 of 9	ENST00000467482.6	NP_000264.2
GPR143	NM_001440781.1 link	c.266C>T	p.Ser89Phe	missense_variant	Exon 2 of 9		NP_001427710.1
GPR143	XM_024452388.2 link	c.14C>T	p.Ser5Phe	missense_variant	Exon 2 of 9		XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GPR143	ENST00000467482.6 link	c.266C>T	p.Ser89Phe	missense_variant	Exon 2 of 9	1	NM_000273.3	ENSP00000417161.1
GPR143	ENST00000447366.5 link	c.14C>T	p.Ser5Phe	missense_variant	Exon 2 of 8	3		ENSP00000390546.2
GPR143	ENST00000431126.1 link	c.14C>T	p.Ser5Phe	missense_variant	Exon 2 of 6	3		ENSP00000406138.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1007603

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

290935

African (AFR)

AF:

0.00

AC:

AN:

24798

American (AMR)

AF:

0.00

AC:

AN:

33245

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18499

East Asian (EAS)

AF:

0.00

AC:

AN:

29658

South Asian (SAS)

AF:

0.00

AC:

AN:

49889

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3934

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

764705

Other (OTH)

AF:

0.00

AC:

AN:

43165

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Nystagmus 6, congenital, X-linked

Pathogenic:1

Jan 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.66

BayesDel_noAF

Pathogenic

0.71

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;D

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;T;T

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;.;.

PhyloP100

8.6

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.8

D;.;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.96

MutPred

0.82

Loss of catalytic residue at S89 (P = 0.0045);.;.;

MVP

1.0

MPC

0.29

ClinPred

1.0

GERP RS

4.5

Varity_R

0.73

gMVP

0.89

Mutation Taster

=13/87

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over