X-9725768-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000273.3(GPR143):c.1193T>C(p.Leu398Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,204,986 control chromosomes in the GnomAD database, including 1 homozygotes. There are 66 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L398F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., 33 hem., cov: 22)
  • Exomes 𝑓: 0.000092 (0 hom. 33 hem.)
• Consequence: GPR143 NM_000273.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0860

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00396052).
• BP6: Variant X-9725768-A-G is Benign according to our data. Variant chrX-9725768-A-G is described in ClinVar as [Benign]. Clinvar id is 1169666.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-9725768-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00106 (118/111120) while in subpopulation AFR AF= 0.00363 (111/30542). AF 95% confidence interval is 0.00309. There are 1 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 33 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR143	NM_000273.3	c.1193T>C	p.Leu398Pro	missense_variant	9/9	ENST00000467482.6
GPR143	XM_024452388.2	c.941T>C	p.Leu314Pro	missense_variant	9/9
GPR143	XM_005274541.4	c.*168T>C		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR143	ENST00000467482.6	c.1193T>C	p.Leu398Pro	missense_variant	9/9	1	NM_000273.3	P1
TBL1X	ENST00000647060.1	c.1554+10765A>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 119 AN: 111069 Hom.: 1 Cov.: 22 AF XY: 0.000992 AC XY: 33 AN XY: 33253

Gnomad AFR AF: 0.00368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000288

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: 0.0000189

Gnomad OTH AF: 0.00203

GnomAD3 exomes AF: 0.000285 AC: 52 AN: 182396 Hom.: 0 AF XY: 0.000179 AC XY: 12 AN XY: 66874

Gnomad AFR exome AF: 0.00313

Gnomad AMR exome AF: 0.000329

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: 0.000221

GnomAD4 exome AF: 0.0000923 AC: 101 AN: 1093866 Hom.: 0 Cov.: 28 AF XY: 0.0000918 AC XY: 33 AN XY: 359402

Gnomad4 AFR exome AF: 0.00262

Gnomad4 AMR exome AF: 0.000369

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: 0.00000358

Gnomad4 OTH exome AF: 0.000327

GnomAD4 genome AF: 0.00106 AC: 118 AN: 111120 Hom.: 1 Cov.: 22 AF XY: 0.000991 AC XY: 33 AN XY: 33314

Gnomad4 AFR AF: 0.00363

Gnomad4 AMR AF: 0.000287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00201

Alfa AF: 0.000137 Hom.: 5

Bravo AF: 0.00114

ESP6500AA AF: 0.00391 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000338 AC: 41

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	1.2
Dann	Benign	0.28
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.0040	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	-0.76	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.14	N
REVEL	Uncertain	0.35
Sift	Benign	0.16	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.050
MVP		0.47
MPC		0.054
ClinPred		0.00039	T
GERP RS		0.25
Varity_R		0.062
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs148263276; hg19: chrX-9693808;