chrX-9746132-G-A

Variant names:

• chrX-9746132-G-A
• rs61733440
• NM_000273.3:c.570C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BS1 BS2

The NM_000273.3(GPR143):​c.570C>T​(p.His190His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000988 in 1,187,424 control chromosomes in the GnomAD database, including 7 homozygotes. There are 263 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., 133 hem., cov: 23)
  • Exomes 𝑓: 0.00055 (4 hom. 130 hem.)
• Consequence: GPR143 NM_000273.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0680
• Publications: 1 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.279).
• BP6: Variant X-9746132-G-A is Benign according to our data. Variant chrX-9746132-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.068 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00517 (579/111895) while in subpopulation AFR AF = 0.0175 (540/30829). AF 95% confidence interval is 0.0163. There are 3 homozygotes in GnomAd4. There are 133 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR143	NM_000273.3	MANE Select	c.570C>T	p.His190His	synonymous	Exon 5 of 9	NP_000264.2
	GPR143	NM_001440781.1		c.570C>T	p.His190His	synonymous	Exon 5 of 9	NP_001427710.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR143	ENST00000467482.6	TSL:1 MANE Select	c.570C>T	p.His190His	synonymous	Exon 5 of 9	ENSP00000417161.1
	GPR143	ENST00000929114.1		c.654C>T	p.His218His	synonymous	Exon 6 of 10	ENSP00000599173.1
	GPR143	ENST00000929113.1		c.570C>T	p.His190His	synonymous	Exon 5 of 9	ENSP00000599172.1

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 577 AN: 111840 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00238

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00793

GnomAD2 exomes AF: 0.00156 AC: 286 AN: 183341 AF XY: 0.000870

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.000552 AC: 594 AN: 1075529 Hom.: 4 Cov.: 28 AF XY: 0.000379 AC XY: 130 AN XY: 343433

African (AFR) AF: 0.0186 AC: 483 AN: 25979

American (AMR) AF: 0.00105 AC: 37 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19230

East Asian (EAS) AF: 0.00 AC: 0 AN: 30121

South Asian (SAS) AF: 0.00 AC: 0 AN: 53667

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4063

European-Non Finnish (NFE) AF: 0.0000146 AC: 12 AN: 821434

Other (OTH) AF: 0.00135 AC: 61 AN: 45334

GnomAD4 genome AF: 0.00517 AC: 579 AN: 111895 Hom.: 3 Cov.: 23 AF XY: 0.00390 AC XY: 133 AN XY: 34067

African (AFR) AF: 0.0175 AC: 540 AN: 30829

American (AMR) AF: 0.00238 AC: 25 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3535

South Asian (SAS) AF: 0.00 AC: 0 AN: 2665

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6081

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53196

Other (OTH) AF: 0.00783 AC: 12 AN: 1532

Alfa AF: 0.000304 Hom.: 1

Bravo AF: 0.00623

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.12
DANN	Benign	0.88
PhyloP100		0.068
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61733440; hg19: chrX-9714172;