rs2314298

Positions:

chrX-133596513-A-G

Variant summary

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

The NM_004484.4(GPC3):c.1500T>C(p.Asp500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,203,953 control chromosomes in the GnomAD database, including 1,127 homozygotes. There are 4,004 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.062 ( 570 hom., 1822 hem., cov: 22)

Exomes 𝑓: 0.0074 ( 557 hom. 2182 hem. )

Consequence

GPC3
NM_004484.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.89

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=-0.9).

BP6

Variant X-133596513-A-G is Benign according to our data. Variant chrX-133596513-A-G is described in ClinVar as [Benign]. Clinvar id is 259405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.88 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GPC3	NM_004484.4 linkuse as main transcript	c.1500T>C	p.Asp500=	synonymous_variant	7/8	ENST00000370818.8
GPC3	NM_001164617.2 linkuse as main transcript	c.1569T>C	p.Asp523=	synonymous_variant	8/9
GPC3	NM_001164618.2 linkuse as main transcript	c.1452T>C	p.Asp484=	synonymous_variant	7/8
GPC3	NM_001164619.2 linkuse as main transcript	c.1338T>C	p.Asp446=	synonymous_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8 linkuse as main transcript	c.1500T>C	p.Asp500=	synonymous_variant	7/8	1	NM_004484.4	P1	P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0622

AC:

6938

AN:

111568

Hom.:

567

Cov.:

AF XY:

0.0536

AC XY:

1808

AN XY:

33756

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0244

Gnomad ASJ

AF:

0.00717

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00113

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.0512

GnomAD3 exomes

AF:

0.0192

AC:

3519

AN:

183229

Hom.:

283

AF XY:

0.0124

AC XY:

838

AN XY:

67761

show subpopulations

Gnomad AFR exome

AF:

0.230

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000918

Gnomad OTH exome

AF:

0.00819

GnomAD4 exome

AF:

0.00741

AC:

8092

AN:

1092330

Hom.:

557

Cov.:

AF XY:

0.00610

AC XY:

2182

AN XY:

357832

show subpopulations

Gnomad4 AFR exome

AF:

0.229

Gnomad4 AMR exome

AF:

0.0135

Gnomad4 ASJ exome

AF:

0.00672

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000463

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000697

Gnomad4 OTH exome

AF:

0.0172

GnomAD4 genome

AF:

0.0624

AC:

6960

AN:

111623

Hom.:

570

Cov.:

AF XY:

0.0539

AC XY:

1822

AN XY:

33821

show subpopulations

Gnomad4 AFR

AF:

0.215

Gnomad4 AMR

AF:

0.0244

Gnomad4 ASJ

AF:

0.00717

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00114

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.0505

Alfa

AF:

0.0327

Hom.:

396

Bravo

AF:

0.0711

EpiCase

AF:

0.00158

EpiControl

AF:

0.00142

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.1500T>C (p.Asp500Asp) causes a synonymous change involving a non-conserved nucleotide with / in silico programs 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 2082/87736 (1/42, 182 homozygotes, 453 hemizygotes), which significantly exceeds the estimated maximum 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 and/or reputable databases/clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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. -

Wilms tumor 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Feb 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.10

DANN

Benign

0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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