X-9741347-CCA-GCC

Variant names:

• chrX-9741347-CCA-GCC
• NM_000273.3:c.874_876delTGGinsGGC
• GPR143 p.Trp292Gly

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1_Very_Strong PM5 PP3

The NM_000273.3(GPR143):​c.874_876delTGGinsGGC​(p.Trp292Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic 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)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.92
• 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: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_000273.3 (GPR143) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.874_876delTGGinsGGC	p.Trp292Gly	missense	N/A	NP_000264.2	P51810
	GPR143	NM_001440781.1		c.874_876delTGGinsGGC	p.Trp292Gly	missense	N/A	NP_001427710.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR143	ENST00000467482.6	TSL:1 MANE Select	c.874_876delTGGinsGGC	p.Trp292Gly	missense	N/A	ENSP00000417161.1	P51810
	GPR143	ENST00000929114.1		c.958_960delTGGinsGGC	p.Trp320Gly	missense	N/A	ENSP00000599173.1
	GPR143	ENST00000929113.1		c.856_858delTGGinsGGC	p.Trp286Gly	missense	N/A	ENSP00000599172.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

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

hg19: chrX-9709387;