X-9743637-G-T

Variant names:

• chrX-9743637-G-T
• rs137852297
• NM_000273.3:c.695C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000273.3(GPR143):​c.695C>A​(p.Thr232Lys) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T232M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.90
• Publications: 9 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):

• 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)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000273.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-9743637-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1213617.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant X-9743637-G-T is Pathogenic according to our data. Variant chrX-9743637-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10518.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR143	NM_000273.3	c.695C>A	p.Thr232Lys	missense_variant	Exon 6 of 9	ENST00000467482.6	NP_000264.2
GPR143	NM_001440781.1	c.695C>A	p.Thr232Lys	missense_variant	Exon 6 of 9		NP_001427710.1
GPR143	XM_024452388.2	c.443C>A	p.Thr148Lys	missense_variant	Exon 6 of 9		XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR143	ENST00000467482.6	c.695C>A	p.Thr232Lys	missense_variant	Exon 6 of 9	1	NM_000273.3	ENSP00000417161.1
GPR143	ENST00000447366.5	c.443C>A	p.Thr148Lys	missense_variant	Exon 6 of 8	3		ENSP00000390546.2
GPR143	ENST00000431126.1	c.443C>A	p.Thr148Lys	missense_variant	Exon 6 of 6	3		ENSP00000406138.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1065804 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 335384

African (AFR) AF: 0.00 AC: 0 AN: 25764

American (AMR) AF: 0.00 AC: 0 AN: 35170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19181

East Asian (EAS) AF: 0.00 AC: 0 AN: 30101

South Asian (SAS) AF: 0.00 AC: 0 AN: 53406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4058

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 812593

Other (OTH) AF: 0.00 AC: 0 AN: 45010

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Ocular albinism, type I Pathogenic:1

Apr 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.
PhyloP100		8.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.79
MutPred		0.76		Gain of helix (P = 0.0093);.;.;
MVP		1.0
MPC		0.31
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.95
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137852297; hg19: chrX-9711677;