rs761660909

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4BP6_ModerateBS2

The NM_004484.4(GPC3):c.326C>T(p.Ala109Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,206,725 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A109E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000012 ( 0 hom. 3 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 9.36

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33161783).

BP6

Variant X-133953061-G-A is Benign according to our data. Variant chrX-133953061-G-A is described in ClinVar as [Benign]. Clinvar id is 578171.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC3	NM_004484.4 linkuse as main transcript	c.326C>T	p.Ala109Val	missense_variant	2/8	ENST00000370818.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8 linkuse as main transcript	c.326C>T	p.Ala109Val	missense_variant	2/8	1	NM_004484.4	P1	P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111671

Hom.:

Cov.:

AF XY:

0.0000886

AC XY:

AN XY:

33855

show subpopulations

Gnomad AFR

AF:

0.0000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000377

Gnomad FIN

AF:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183225

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67733

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.0000627

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1095054

Hom.:

Cov.:

AF XY:

0.00000832

AC XY:

AN XY:

360576

show subpopulations

Gnomad4 AFR exome

AF:

0.0000759

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000555

Gnomad4 FIN exome

AF:

0.0000988

Gnomad4 NFE exome

AF:

0.00000357

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000448

AC:

AN:

111671

Hom.:

Cov.:

AF XY:

0.0000886

AC XY:

AN XY:

33855

show subpopulations

Gnomad4 AFR

AF:

0.0000652

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000377

Gnomad4 FIN

AF:

0.000166

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Wilms tumor 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.30

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

T;D

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.25

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.77

P;.

Vest4

0.55

MVP

0.71

MPC

0.26

ClinPred

0.22

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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