NM_000273.3:c.1189G>T

Variant names:

• chrX-9725772-C-A
• rs1373645423
• NM_000273.3:c.1189G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000273.3(GPR143):​c.1189G>T​(p.Ala397Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000901 in 110,970 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.438
• 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08800006).

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.1189G>T	p.Ala397Ser	missense	Exon 9 of 9	NP_000264.2	P51810
	GPR143	NM_001440781.1		c.*164G>T		3_prime_UTR	Exon 9 of 9	NP_001427710.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR143	ENST00000467482.6	TSL:1 MANE Select	c.1189G>T	p.Ala397Ser	missense	Exon 9 of 9	ENSP00000417161.1	P51810
	GPR143	ENST00000929114.1		c.1273G>T	p.Ala425Ser	missense	Exon 10 of 10	ENSP00000599173.1
	GPR143	ENST00000929113.1		c.1171G>T	p.Ala391Ser	missense	Exon 9 of 9	ENSP00000599172.1

Frequencies

GnomAD3 genomes AF: 0.00000901 AC: 1 AN: 110970 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000329

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

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.13e-7 AC: 1 AN: 1095084 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 360532

African (AFR) AF: 0.0000380 AC: 1 AN: 26340

American (AMR) AF: 0.00 AC: 0 AN: 35179

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 53930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839447

Other (OTH) AF: 0.00 AC: 0 AN: 45992

GnomAD4 genome AF: 0.00000901 AC: 1 AN: 110970 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 33156

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

African (AFR) AF: 0.0000329 AC: 1 AN: 30436

American (AMR) AF: 0.00 AC: 0 AN: 10444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00 AC: 0 AN: 2621

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5923

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52987

Other (OTH) AF: 0.00 AC: 0 AN: 1470

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	0.074
DANN	Benign	0.47
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.088	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.1	L
PhyloP100		-0.44
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.32
Sift	Benign	0.18	T
Sift4G	Uncertain	0.054	T
Polyphen		0.042	B
Vest4		0.068
MutPred		0.37		Gain of glycosylation at A397 (P = 0.0219)
MVP		0.89
MPC		0.043
ClinPred		0.052	T
GERP RS		-5.8
Varity_R		0.065
gMVP		0.11
Mutation Taster		=99/1	polymorphism

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: rs1373645423; hg19: chrX-9693812;