rs3044

Variant names:

• chrX-9725612-G-A
• rs3044
• NM_000273.3:c.*134C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000273.3(GPR143):​c.*134C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 506,144 control chromosomes in the GnomAD database, including 19,753 homozygotes. There are 41,194 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (7896 hom., 11397 hem., cov: 22)
  • Exomes 𝑓: 0.24 (11857 hom. 29797 hem.)
• Consequence: GPR143 NM_000273.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.143
• 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]

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]

TBL1X Gene-Disease associations (from GenCC):

• hypothyroidism, congenital, nongoitrous, 8

  Inheritance: XL, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-9725612-G-A is Benign according to our data. Variant chrX-9725612-G-A is described in ClinVar as Benign. ClinVar VariationId is 1294751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR143	NM_000273.3	c.*134C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000467482.6	NP_000264.2
GPR143	NM_001440781.1	c.*324C>T		3_prime_UTR_variant	Exon 9 of 9		NP_001427710.1
GPR143	XM_024452388.2	c.*134C>T		3_prime_UTR_variant	Exon 9 of 9		XP_024308156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR143	ENST00000467482.6	c.*134C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_000273.3	ENSP00000417161.1
TBL1X	ENST00000647060.1	c.1554+10609G>A		intron_variant	Intron 15 of 15			ENSP00000495467.1

Frequencies

GnomAD3 genomes AF: 0.362 AC: 39898 AN: 110264 Hom.: 7879 Cov.: 22

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.265

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.238 AC: 94198 AN: 395828 Hom.: 11857 Cov.: 5 AF XY: 0.231 AC XY: 29797 AN XY: 129124

African (AFR) AF: 0.751 AC: 8837 AN: 11767

American (AMR) AF: 0.473 AC: 10935 AN: 23111

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 2650 AN: 12314

East Asian (EAS) AF: 0.674 AC: 15869 AN: 23545

South Asian (SAS) AF: 0.182 AC: 5963 AN: 32750

European-Finnish (FIN) AF: 0.192 AC: 6182 AN: 32141

Middle Eastern (MID) AF: 0.216 AC: 564 AN: 2608

European-Non Finnish (NFE) AF: 0.157 AC: 37087 AN: 235490

Other (OTH) AF: 0.276 AC: 6111 AN: 22102

GnomAD4 genome AF: 0.362 AC: 39957 AN: 110316 Hom.: 7896 Cov.: 22 AF XY: 0.349 AC XY: 11397 AN XY: 32628

African (AFR) AF: 0.739 AC: 22181 AN: 30030

American (AMR) AF: 0.438 AC: 4545 AN: 10369

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 585 AN: 2634

East Asian (EAS) AF: 0.633 AC: 2171 AN: 3432

South Asian (SAS) AF: 0.174 AC: 456 AN: 2618

European-Finnish (FIN) AF: 0.183 AC: 1090 AN: 5945

Middle Eastern (MID) AF: 0.273 AC: 59 AN: 216

European-Non Finnish (NFE) AF: 0.155 AC: 8205 AN: 52896

Other (OTH) AF: 0.373 AC: 561 AN: 1505

Alfa AF: 0.276 Hom.: 5927

Bravo AF: 0.410

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.45
DANN	Benign	0.52
PhyloP100		-0.14
Mutation Taster		=100/0	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: rs3044; hg19: chrX-9693652; COSMIC: COSV66632069;