rs62635045

Variant names:

• chrX-9741349-A-C
• rs62635045
• NM_000273.3:c.874T>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000273.3(GPR143):​c.874T>G​(p.Trp292Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000371 in 808,031 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004300090: Experimental studies have shown that this missense change affects GPR143 function (PMID:11115845)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W292C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.92
• 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004300090: Experimental studies have shown that this missense change affects GPR143 function (PMID: 11115845).; SCV007096612: Mutant constructs transfected into COS7 cells resulted in defective glycosylation and protein retention in the ER (PMID: 11115845). In addition, PC12 cells harbouring the mutant construct failed to inhibit neurite outgrowth compared to the WT (PMID: 31606330)
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-9741347-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 98649.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-9741349-A-C is Pathogenic according to our data. Variant chrX-9741349-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 98647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR143	NM_000273.3	MANE Select	c.874T>G	p.Trp292Gly	missense	Exon 7 of 9	NP_000264.2	P51810
	GPR143	NM_001440781.1		c.874T>G	p.Trp292Gly	missense	Exon 7 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.874T>G	p.Trp292Gly	missense	Exon 7 of 9	ENSP00000417161.1	P51810
	GPR143	ENST00000929114.1		c.958T>G	p.Trp320Gly	missense	Exon 8 of 10	ENSP00000599173.1
	GPR143	ENST00000929113.1		c.856T>G	p.Trp286Gly	missense	Exon 7 of 9	ENSP00000599172.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000371 AC: 3 AN: 808031 Hom.: 0 Cov.: 13 AF XY: 0.00000443 AC XY: 1 AN XY: 225887

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20987

American (AMR) AF: 0.00 AC: 0 AN: 33504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17307

East Asian (EAS) AF: 0.00 AC: 0 AN: 28623

South Asian (SAS) AF: 0.00 AC: 0 AN: 47056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39705

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2956

European-Non Finnish (NFE) AF: 0.00000516 AC: 3 AN: 581674

Other (OTH) AF: 0.00 AC: 0 AN: 36219

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Albinism (1)
1	-	-	GPR143-related foveal hypoplasia (1)
1	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.93		Loss of helix (P = 0.0444)
MVP		1.0
MPC		0.35
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.98
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62635045; hg19: chrX-9709389;