rs1060502171

Positions:

• chrX-133754159-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_004484.4(GPC3):​c.355G>T​(p.Val119Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.00024 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.17

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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC3	NM_004484.4	c.355G>T	p.Val119Phe	missense_variant	3/8	ENST00000370818.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8	c.355G>T	p.Val119Phe	missense_variant	3/8	1	NM_004484.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 89522 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 21534 FAILED QC

Gnomad AFR AF: 0.0000837

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: 0.000237 AC: 221 AN: 930592 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 271614

Gnomad4 AFR exome AF: 0.000452

Gnomad4 AMR exome AF: 0.000761

Gnomad4 ASJ exome AF: 0.000407

Gnomad4 EAS exome AF: 0.000583

Gnomad4 SAS exome AF: 0.000585

Gnomad4 FIN exome AF: 0.0000798

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.000302

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000223 AC: 2 AN: 89555 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 21569

Gnomad4 AFR AF: 0.0000835

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

May 21, 2019

The p.V119F variant (also known as c.355G>T), located in coding exon 3 of the GPC3 gene, results from a G to T substitution at nucleotide position 355. The valine at codon 119 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Wilms tumor 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2023

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 119 of the GPC3 protein (p.Val119Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 408889). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GPC3 protein function. 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.80
MutPred		0.76		Loss of ubiquitination at K123 (P = 0.1498);Loss of ubiquitination at K123 (P = 0.1498);.;
MVP		0.83
MPC		0.28
ClinPred		0.072	T
GERP RS		5.3
Varity_R		0.69
gMVP		0.94

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: rs1060502171; hg19: chrX-132888186;