X-9725804-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000273.3(GPR143):c.1157G>A(p.Ser386Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,097,322 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S386G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000018 (0 hom. 9 hem.)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20380384).
• BS2: High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR143	NM_000273.3	c.1157G>A	p.Ser386Asn	missense_variant	9/9	ENST00000467482.6
GPR143	XM_024452388.2	c.905G>A	p.Ser302Asn	missense_variant	9/9
GPR143	XM_005274541.4	c.*132G>A		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR143	ENST00000467482.6	c.1157G>A	p.Ser386Asn	missense_variant	9/9	1	NM_000273.3	P1
TBL1X	ENST00000647060.1	c.1554+10801C>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.0000165 AC: 3 AN: 182266 Hom.: 0 AF XY: 0.0000449 AC XY: 3 AN XY: 66748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 20 AN: 1097322 Hom.: 0 Cov.: 29 AF XY: 0.0000248 AC XY: 9 AN XY: 362690

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000214

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 21

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.1157G>A (p.S386N) alteration is located in exon 9 (coding exon 9) of the GPR143 gene. This alteration results from a G to A substitution at nucleotide position 1157, causing the serine (S) at amino acid position 386 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 386 of the GPR143 protein (p.Ser386Asn). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with GPR143-related conditions. This variant is present in population databases (rs770745735, gnomAD 0.004%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	13
Dann	Benign	0.96
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.35	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.42
Sift	Benign	0.063	T
Sift4G	Benign	0.13	T
Polyphen		0.014	B
Vest4		0.10
MutPred		0.40		Loss of phosphorylation at S386 (P = 0.079);
MVP		0.94
MPC		0.041
ClinPred		0.049	T
GERP RS		3.4
Varity_R		0.093
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs770745735; hg19: chrX-9693844;