X-9743555-G-T

Variant names:

• chrX-9743555-G-T
• rs3788938
• NM_000273.3:c.767+10C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000273.3(GPR143):​c.767+10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,013,890 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.0000089 (0 hom. 2 hem.)
• Consequence: GPR143 NM_000273.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.347
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000992 (11/110892) while in subpopulation AFR AF = 0.000359 (11/30614). AF 95% confidence interval is 0.000201. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR143	NM_000273.3	c.767+10C>A		intron_variant	Intron 6 of 8	ENST00000467482.6	NP_000264.2
GPR143	NM_001440781.1	c.767+10C>A		intron_variant	Intron 6 of 8		NP_001427710.1
GPR143	XM_024452388.2	c.515+10C>A		intron_variant	Intron 6 of 8		XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR143	ENST00000467482.6	c.767+10C>A		intron_variant	Intron 6 of 8	1	NM_000273.3	ENSP00000417161.1
GPR143	ENST00000447366.5	c.515+10C>A		intron_variant	Intron 6 of 7	3		ENSP00000390546.2
GPR143	ENST00000431126.1	c.*10C>A		downstream_gene_variant		3		ENSP00000406138.1

Frequencies

GnomAD3 genomes AF: 0.0000992 AC: 11 AN: 110840 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182915 AF XY: 0.00

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000886 AC: 8 AN: 902998 Hom.: 0 Cov.: 17 AF XY: 0.00000760 AC XY: 2 AN XY: 263072

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

African (AFR) AF: 0.000221 AC: 5 AN: 22612

American (AMR) AF: 0.0000572 AC: 2 AN: 34964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18212

East Asian (EAS) AF: 0.00 AC: 0 AN: 29345

South Asian (SAS) AF: 0.00 AC: 0 AN: 50158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40417

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3721

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 664044

Other (OTH) AF: 0.0000253 AC: 1 AN: 39525

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.012412), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000992 AC: 11 AN: 110892 Hom.: 0 Cov.: 22 AF XY: 0.0000603 AC XY: 2 AN XY: 33150

African (AFR) AF: 0.000359 AC: 11 AN: 30614

American (AMR) AF: 0.00 AC: 0 AN: 10376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3489

South Asian (SAS) AF: 0.00 AC: 0 AN: 2619

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52905

Other (OTH) AF: 0.00 AC: 0 AN: 1507

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.0
DANN	Benign	0.48
PhyloP100		-0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3788938; hg19: chrX-9711595;