X-133754029-T-C

Position:

chrX-133754029-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004484.4(GPC3):c.485A>G(p.Asn162Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,208,656 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000044 ( 0 hom. 13 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.754

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05715877).

BP6

Variant X-133754029-T-C is Benign according to our data. Variant chrX-133754029-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476656.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}. Variant chrX-133754029-T-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPC3	NM_004484.4 linkuse as main transcript	c.485A>G	p.Asn162Ser	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.485A>G	p.Asn162Ser	missense_variant	3/8	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111503

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33703

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000941

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183028

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67616

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000368

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1097101

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

362465

show subpopulations

Gnomad4 AFR exome

AF:

0.000227

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000428

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000538

AC:

AN:

111555

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

33765

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000942

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GPC3: BP4, BS2 -

Simpson-Golabi-Behmel syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 28, 2023

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2021

This alteration is classified as likely 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 22, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jan 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.91

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.29

T;.;.

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.057

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.79

N;N;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.60

N;N;.

REVEL

Benign

0.13

Sift

Benign

0.77

T;T;.

Sift4G

Benign

0.89

T;T;T

Polyphen

0.0050

B;.;.

Vest4

0.083

MVP

0.64

MPC

0.15

ClinPred

0.024

GERP RS

4.3

Varity_R

0.066

gMVP

0.24

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