X-9760811-G-T

Variant names:

• chrX-9760811-G-T
• rs137852298
• NM_000273.3:c.266C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000273.3(GPR143):​c.266C>A​(p.Ser89Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000992 in 1,007,597 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S89F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.9e-7 (0 hom. 1 hem.)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.55
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

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.266C>A	p.Ser89Tyr	missense	Exon 2 of 9	NP_000264.2	P51810
	GPR143	NM_001440781.1		c.266C>A	p.Ser89Tyr	missense	Exon 2 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.266C>A	p.Ser89Tyr	missense	Exon 2 of 9	ENSP00000417161.1	P51810
	GPR143	ENST00000929114.1		c.266C>A	p.Ser89Tyr	missense	Exon 2 of 10	ENSP00000599173.1
	GPR143	ENST00000929113.1		c.266C>A	p.Ser89Tyr	missense	Exon 2 of 9	ENSP00000599172.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.92e-7 AC: 1 AN: 1007597 Hom.: 0 Cov.: 22 AF XY: 0.00000344 AC XY: 1 AN XY: 290929

African (AFR) AF: 0.00 AC: 0 AN: 24796

American (AMR) AF: 0.00 AC: 0 AN: 33245

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18499

East Asian (EAS) AF: 0.00 AC: 0 AN: 29658

South Asian (SAS) AF: 0.00 AC: 0 AN: 49890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3934

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 764700

Other (OTH) AF: 0.00 AC: 0 AN: 43165

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.83		Loss of sheet (P = 0.0104)
MVP		0.96
MPC		0.31
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.83
gMVP		0.88
Mutation Taster		=19/81	disease causing

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: rs137852298; hg19: chrX-9728851;