rs148021273

Positions:

chrX-133754155-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004484.4(GPC3):c.359G>A(p.Arg120His) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,163,014 control chromosomes in the GnomAD database, including 1 homozygotes. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., 10 hem., cov: 21)

Exomes 𝑓: 0.00011 ( 1 hom. 30 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.61

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:

GPC3 (HGNC:):

GPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027450472).

BP6

Variant X-133754155-C-T is Benign according to our data. Variant chrX-133754155-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 415271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-133754155-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPC3	NM_004484.4 linkuse as main transcript	c.359G>A	p.Arg120His	missense_variant	3/8	ENST00000370818.8	NP_004475.1	P51654-1Q53H15I6QTG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8 linkuse as main transcript	c.359G>A	p.Arg120His	missense_variant	3/8	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.000536

AC:

AN:

100737

Hom.:

Cov.:

AF XY:

0.000387

AC XY:

AN XY:

25873

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00121

Gnomad SAS

AF:

0.000460

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000398

Gnomad OTH

AF:

0.00153

GnomAD3 exomes

AF:

0.000313

AC:

AN:

172561

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

60581

show subpopulations

Gnomad AFR exome

AF:

0.00180

Gnomad AMR exome

AF:

0.0000766

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00159

Gnomad SAS exome

AF:

0.000178

Gnomad FIN exome

AF:

0.000260

Gnomad NFE exome

AF:

0.0000130

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

116

AN:

1062245

Hom.:

Cov.:

AF XY:

0.0000895

AC XY:

AN XY:

335055

show subpopulations

Gnomad4 AFR exome

AF:

0.00177

Gnomad4 AMR exome

AF:

0.000207

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000878

Gnomad4 SAS exome

AF:

0.0000999

Gnomad4 FIN exome

AF:

0.000226

Gnomad4 NFE exome

AF:

0.0000123

Gnomad4 OTH exome

AF:

0.000313

GnomAD4 genome

AF:

0.000536

AC:

AN:

100769

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

AN XY:

25913

show subpopulations

Gnomad4 AFR

AF:

0.00126

Gnomad4 AMR

AF:

0.00125

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00121

Gnomad4 SAS

AF:

0.000463

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000398

Gnomad4 OTH

AF:

0.00151

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.000759

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000297

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	This variant is associated with the following publications: (PMID: 28497333) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

GPC3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jun 24, 2021

- -

Wilms tumor 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;.;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.027

T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.0

M;M;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.7

D;D;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0050

D;D;.

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.47

MVP

0.59

MPC

0.30

ClinPred

0.041

GERP RS

5.3

Varity_R

0.68

gMVP

0.66

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