X-133536131-A-C

Position:

• chrX-133536131-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004484.4(GPC3):​c.1736T>G​(p.Val579Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. V579M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.823

Genes affected

GPC3 (HGNC:4451): (glypican 3) Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20411089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC3	NM_004484.4	c.1736T>G	p.Val579Gly	missense_variant	8/8	ENST00000370818.8
GPC3	NM_001164617.2	c.1805T>G	p.Val602Gly	missense_variant	9/9
GPC3	NM_001164618.2	c.1688T>G	p.Val563Gly	missense_variant	8/8
GPC3	NM_001164619.2	c.1574T>G	p.Val525Gly	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8	c.1736T>G	p.Val579Gly	missense_variant	8/8	1	NM_004484.4	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183020 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67574

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.17e-7 AC: 1 AN: 1090814 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 1 AN XY: 357310

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wilms tumor 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2023

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 579 of the GPC3 protein (p.Val579Gly). This variant is present in population databases (no rsID available, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with GPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 953514). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.98	N;N;.
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.025	B;.;.
Vest4		0.25
MutPred		0.44		Loss of stability (P = 1e-04);.;.;
MVP		0.92
MPC		0.28
ClinPred		0.21	T
GERP RS		1.4
Varity_R		0.21
gMVP		0.81

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: rs1197981146; hg19: chrX-132670159;