rs148021273

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R120C) has been classified 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:7

Conservation

PhyloP100: 4.61

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Simpson-Golabi-Behmel syndrome
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Simpson-Golabi-Behmel syndrome type 1
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

GPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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 Benign/Likely_benign. ClinVar VariationId is 415271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000536 (54/100769) while in subpopulation AFR AF = 0.00126 (34/27035). AF 95% confidence interval is 0.000925. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4 link	c.359G>A	p.Arg120His	missense_variant	Exon 3 of 8	ENST00000370818.8	NP_004475.1	P51654-1Q53H15I6QTG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8 link	c.359G>A	p.Arg120His	missense_variant	Exon 3 of 8	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.000536

AC:

AN:

100737

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000313

AC:

AN:

172561

AF XY:

0.000281

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 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

African (AFR)

AF:

0.00177

AC:

AN:

25368

American (AMR)

AF:

0.000207

AC:

AN:

33868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18786

East Asian (EAS)

AF:

0.000878

AC:

AN:

29629

South Asian (SAS)

AF:

0.0000999

AC:

AN:

50073

European-Finnish (FIN)

AF:

0.000226

AC:

AN:

39767

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3832

European-Non Finnish (NFE)

AF:

0.0000123

AC:

AN:

816189

Other (OTH)

AF:

0.000313

AC:

AN:

44733

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000536

AC:

AN:

100769

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

AN XY:

25913

show subpopulations

African (AFR)

AF:

0.00126

AC:

AN:

27035

American (AMR)

AF:

0.00125

AC:

AN:

8820

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2536

East Asian (EAS)

AF:

0.00121

AC:

AN:

3301

South Asian (SAS)

AF:

0.000463

AC:

AN:

2162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

193

European-Non Finnish (NFE)

AF:

0.0000398

AC:

AN:

50281

Other (OTH)

AF:

0.00151

AC:

AN:

1326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 18, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28497333) -

Simpson-Golabi-Behmel syndrome type 1

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GPC3-related disorder

Benign:1

Aug 06, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jun 24, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Wilms tumor 1

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

4.6

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

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.68

gMVP

0.66

Mutation Taster

=52/48

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over