X-9765714-C-A

Variant names:

• chrX-9765714-C-A
• rs62635018
• NM_000273.3:c.104G>T
• GPR143 p.Gly35Val

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000273.3(GPR143):​c.104G>T​(p.Gly35Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000399 in 1,003,693 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G35D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000040 (0 hom. 1 hem.)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

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.104G>T	p.Gly35Val	missense	Exon 1 of 9	NP_000264.2	P51810
	GPR143	NM_001440781.1		c.104G>T	p.Gly35Val	missense	Exon 1 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.104G>T	p.Gly35Val	missense	Exon 1 of 9	ENSP00000417161.1	P51810
	GPR143	ENST00000929114.1		c.104G>T	p.Gly35Val	missense	Exon 1 of 10	ENSP00000599173.1
	GPR143	ENST00000929113.1		c.104G>T	p.Gly35Val	missense	Exon 1 of 9	ENSP00000599172.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000399 AC: 4 AN: 1003693 Hom.: 0 Cov.: 30 AF XY: 0.00000309 AC XY: 1 AN XY: 323699

African (AFR) AF: 0.00 AC: 0 AN: 21382

American (AMR) AF: 0.00 AC: 0 AN: 23943

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17340

East Asian (EAS) AF: 0.00 AC: 0 AN: 22631

South Asian (SAS) AF: 0.00 AC: 0 AN: 46280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25743

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2981

European-Non Finnish (NFE) AF: 0.00000499 AC: 4 AN: 801021

Other (OTH) AF: 0.00 AC: 0 AN: 42372

GnomAD4 genome Cov.: 25

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.38	N
REVEL	Pathogenic	0.66
Sift	Benign	0.99	T
Sift4G	Uncertain	0.025	D
PromoterAI		-0.0014	Neutral
Varity_R		0.26
gMVP		0.70
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs62635018;

hg19: chrX-9733754;