X-133692376-C-T

Position:

chrX-133692376-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000370818.8(GPC3):c.1285G>A(p.Val429Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,210,255 control chromosomes in the GnomAD database, including 24 homozygotes. There are 1,849 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V429A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., 115 hem., cov: 24)

Exomes 𝑓: 0.0047 ( 21 hom. 1734 hem. )

Consequence

GPC3
ENST00000370818.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 2.92

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008226454).

BP6

Variant X-133692376-C-T is Benign according to our data. Variant chrX-133692376-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-133692376-C-T is described in Lovd as [Likely_benign]. Variant chrX-133692376-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00469 (5144/1097034) while in subpopulation AMR AF= 0.0182 (641/35193). AF 95% confidence interval is 0.017. There are 21 homozygotes in gnomad4_exome. There are 1734 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPC3	NM_004484.4 linkuse as main transcript	c.1285G>A	p.Val429Met	missense_variant	5/8	ENST00000370818.8	NP_004475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8 linkuse as main transcript	c.1285G>A	p.Val429Met	missense_variant	5/8	1	NM_004484.4	ENSP00000359854	P1	P51654-1

Frequencies

GnomAD3 genomes

AF:

0.00350

AC:

396

AN:

113168

Hom.:

Cov.:

AF XY:

0.00326

AC XY:

115

AN XY:

35304

show subpopulations

Gnomad AFR

AF:

0.00112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00338

Gnomad EAS

AF:

0.00138

Gnomad SAS

AF:

0.00432

Gnomad FIN

AF:

0.000476

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00404

Gnomad OTH

AF:

0.00328

GnomAD3 exomes

AF:

0.00625

AC:

1146

AN:

183404

Hom.:

AF XY:

0.00587

AC XY:

398

AN XY:

67854

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.0205

Gnomad ASJ exome

AF:

0.00681

Gnomad EAS exome

AF:

0.00152

Gnomad SAS exome

AF:

0.00624

Gnomad FIN exome

AF:

0.000125

Gnomad NFE exome

AF:

0.00412

Gnomad OTH exome

AF:

0.00817

GnomAD4 exome

AF:

0.00469

AC:

5144

AN:

1097034

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

1734

AN XY:

362442

show subpopulations

Gnomad4 AFR exome

AF:

0.00118

Gnomad4 AMR exome

AF:

0.0182

Gnomad4 ASJ exome

AF:

0.00594

Gnomad4 EAS exome

AF:

0.000861

Gnomad4 SAS exome

AF:

0.00519

Gnomad4 FIN exome

AF:

0.000568

Gnomad4 NFE exome

AF:

0.00452

Gnomad4 OTH exome

AF:

0.00452

GnomAD4 genome

AF:

0.00351

AC:

397

AN:

113221

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

115

AN XY:

35367

show subpopulations

Gnomad4 AFR

AF:

0.00112

Gnomad4 AMR

AF:

0.0104

Gnomad4 ASJ

AF:

0.00338

Gnomad4 EAS

AF:

0.00139

Gnomad4 SAS

AF:

0.00434

Gnomad4 FIN

AF:

0.000476

Gnomad4 NFE

AF:

0.00404

Gnomad4 OTH

AF:

0.00324

Alfa

AF:

0.00415

Hom.:

191

Bravo

AF:

0.00436

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00450

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00576

AC:

699

EpiCase

AF:

0.00491

EpiControl

AF:

0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2018	- -
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.1285G>A (p.Val429Met) causes a missense change involving a conserved nucleotide with 2/3 in silico programs (SNPs&GO and MutationTaster not captured here due to low reliability index and p-value, respectively) predict a "benign" outcome, 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 511/87700 (1/171, 188 hemizygotes, 5 homozygotes), 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. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 09, 2017	- -

not specified

Benign:2Other:1

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

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

May 04, 2016

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

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.77

T;T;T

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.4

M;.;.

MutationTaster

Benign

0.70

D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.0

N;N;.

REVEL

Benign

0.16

Sift

Uncertain

0.013

D;D;.

Sift4G

Uncertain

0.010

D;D;D

Polyphen

0.43

B;.;.

Vest4

0.37

MVP

0.76

MPC

0.70

ClinPred

0.022

GERP RS

5.1

Varity_R

0.26

gMVP

0.59

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