X-9739481-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3 BP6_Moderate BS1 BS2

The NM_000273.3(GPR143):c.1120+4A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.0014 in 1,175,233 control chromosomes in the GnomAD database, including 10 homozygotes. There are 447 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (3 hom., 226 hem., cov: 23)
  • Exomes 𝑓: 0.00081 (7 hom. 221 hem.)
• Consequence: GPR143 NM_000273.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9929
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 5.02

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]

LOC105373126 (HGNC:):

TBL1X (HGNC:11585): (transducin beta like 1 X-linked) The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This encoded protein is found as a subunit in corepressor SMRT (silencing mediator for retinoid and thyroid receptors) complex along with histone deacetylase 3 protein. This gene is located adjacent to the ocular albinism gene and it is thought to be involved in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype. Four transcript variants encoding two different isoforms have been found for this gene. This gene is highly similar to the Y chromosome TBL1Y gene. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant X-9739481-T-C is Benign according to our data. Variant chrX-9739481-T-C is described in ClinVar as [Benign]. Clinvar id is 719864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-9739481-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.007 (785/112146) while in subpopulation AFR AF= 0.024 (742/30902). AF 95% confidence interval is 0.0226. There are 3 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR143	NM_000273.3	c.1120+4A>G		splice_donor_region_variant, intron_variant		ENST00000467482.6
LOC105373126	XR_950507.2	n.1620+762T>C		intron_variant, non_coding_transcript_variant
GPR143	XM_005274541.4	c.1120+4A>G		splice_donor_region_variant, intron_variant
GPR143	XM_024452388.2	c.868+4A>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR143	ENST00000467482.6	c.1120+4A>G		splice_donor_region_variant, intron_variant		1	NM_000273.3	P1
TBL1X	ENST00000647060.1	c.1555-1301T>C		intron_variant
GPR143	ENST00000487206.1	n.235+4A>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 781 AN: 112091 Hom.: 3 Cov.: 23 AF XY: 0.00656 AC XY: 225 AN XY: 34273

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00293

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00330

GnomAD3 exomes AF: 0.00222 AC: 383 AN: 172678 Hom.: 3 AF XY: 0.00136 AC XY: 79 AN XY: 58130

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000572

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.000931

GnomAD4 exome AF: 0.000814 AC: 865 AN: 1063087 Hom.: 7 Cov.: 27 AF XY: 0.000661 AC XY: 221 AN XY: 334511

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000334

Gnomad4 SAS exome AF: 0.0000380

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000481

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00700 AC: 785 AN: 112146 Hom.: 3 Cov.: 23 AF XY: 0.00658 AC XY: 226 AN XY: 34338

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.00292

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00392

Alfa AF: 0.00386 Hom.: 14

Bravo AF: 0.00793

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	24
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: -20
DS_DL_spliceai		0.28		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs151226761; hg19: chrX-9707521;