rs58933950

Variant names:

• chrX-9759332-C-T
• rs58933950
• NM_000273.3:c.455G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_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: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 6.79
• Publications: 3 publications found

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):

• GPR143-related foveal hypoplasia

  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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR143	NM_000273.3	MANE Select	c.455G>A	p.Ser152Asn	missense splice_region	Exon 3 of 9	NP_000264.2	P51810
	GPR143	NM_001440781.1		c.455G>A	p.Ser152Asn	missense splice_region	Exon 3 of 9	NP_001427710.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR143	ENST00000467482.6	TSL:1 MANE Select	c.455G>A	p.Ser152Asn	missense splice_region	Exon 3 of 9	ENSP00000417161.1	P51810
	GPR143	ENST00000929114.1		c.455G>A	p.Arg152Lys	missense splice_region	Exon 3 of 10	ENSP00000599173.1
	GPR143	ENST00000929113.1		c.455G>A	p.Ser152Asn	missense splice_region	Exon 3 of 9	ENSP00000599172.1

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

African (AFR) AF: 0.00 AC: 0 AN: 25083

American (AMR) AF: 0.00 AC: 0 AN: 33770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18835

East Asian (EAS) AF: 0.00 AC: 0 AN: 29302

South Asian (SAS) AF: 0.00 AC: 0 AN: 50849

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39699

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3988

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 790111

Other (OTH) AF: 0.00 AC: 0 AN: 44055

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Ocular albinism, type I (2)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.69
Sift	Benign	0.077	T
Sift4G	Uncertain	0.016	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
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs58933950; hg19: chrX-9727372;