rs61754631

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004484.4(GPC3):c.1626A>G(p.Ala542=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,201,163 control chromosomes in the GnomAD database, including 837 homozygotes. There are 3,145 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 417 hom., 1428 hem., cov: 20)

Exomes 𝑓: 0.0060 ( 420 hom. 1717 hem. )

Consequence

GPC3
NM_004484.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.239

Variant links:

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]

GPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant X-133536241-T-C is Benign according to our data. Variant chrX-133536241-T-C is described in ClinVar as [Benign]. Clinvar id is 137490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.239 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GPC3	NM_004484.4 linkuse as main transcript	c.1626A>G	p.Ala542=	synonymous_variant	8/8	ENST00000370818.8
GPC3	NM_001164617.2 linkuse as main transcript	c.1695A>G	p.Ala565=	synonymous_variant	9/9
GPC3	NM_001164618.2 linkuse as main transcript	c.1578A>G	p.Ala526=	synonymous_variant	8/8
GPC3	NM_001164619.2 linkuse as main transcript	c.1464A>G	p.Ala488=	synonymous_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8 linkuse as main transcript	c.1626A>G	p.Ala542=	synonymous_variant	8/8	1	NM_004484.4	P1	P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0530

AC:

5803

AN:

109415

Hom.:

415

Cov.:

AF XY:

0.0447

AC XY:

1416

AN XY:

31709

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0198

Gnomad ASJ

AF:

0.00686

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000806

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00844

Gnomad NFE

AF:

0.000607

Gnomad OTH

AF:

0.0439

GnomAD3 exomes

AF:

0.0163

AC:

2981

AN:

182961

Hom.:

219

AF XY:

0.0103

AC XY:

694

AN XY:

67551

show subpopulations

Gnomad AFR exome

AF:

0.200

Gnomad AMR exome

AF:

0.00831

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000503

Gnomad OTH exome

AF:

0.00685

GnomAD4 exome

AF:

0.00601

AC:

6564

AN:

1091692

Hom.:

420

Cov.:

AF XY:

0.00481

AC XY:

1717

AN XY:

357228

show subpopulations

Gnomad4 AFR exome

AF:

0.197

Gnomad4 AMR exome

AF:

0.00991

Gnomad4 ASJ exome

AF:

0.00672

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000333

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000255

Gnomad4 OTH exome

AF:

0.0135

GnomAD4 genome

AF:

0.0532

AC:

5819

AN:

109471

Hom.:

417

Cov.:

AF XY:

0.0449

AC XY:

1428

AN XY:

31775

show subpopulations

Gnomad4 AFR

AF:

0.184

Gnomad4 AMR

AF:

0.0198

Gnomad4 ASJ

AF:

0.00686

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000808

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000607

Gnomad4 OTH

AF:

0.0433

Alfa

AF:

0.0282

Hom.:

163

Bravo

AF:

0.0613

EpiCase

AF:

0.00104

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Simpson-Golabi-Behmel syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 05, 2016

Variant summary: The GPC3 variant, c.1626A>G (p.Ala542Ala) causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico tools via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1792/87714 (1/48, 141 homozygotes, 396 hemizygotes), which significantly exceeds the estimated maxium expected allele frequency for a pathogenic GPC3 variant of 1/10000000. The variant of interest, to our knowledge, has not been reported in affected individuals via publications. A reputable clinical laboratory cites the variant as "benign." Therefore, the variant of interest is classified as Benign. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Feb 24, 2020

- -

Wilms tumor 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

Cadd

Benign

2.2

Dann

Benign

0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over