rs759543703

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_004484.4(GPC3):c.1561C>T(p.Arg521Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,207,360 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.73

Publications

6 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34059727).

BP6

Variant X-133596452-G-A is Benign according to our data. Variant chrX-133596452-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568782.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4 link	c.1561C>T	p.Arg521Cys	missense_variant	Exon 7 of 8	ENST00000370818.8	NP_004475.1	P51654-1Q53H15I6QTG3
GPC3	NM_001164617.2 link	c.1630C>T	p.Arg544Cys	missense_variant	Exon 8 of 9		NP_001158089.1	P51654-3Q53H15
GPC3	NM_001164618.2 link	c.1513C>T	p.Arg505Cys	missense_variant	Exon 7 of 8		NP_001158090.1	Q53H15B4DTD8
GPC3	NM_001164619.2 link	c.1399C>T	p.Arg467Cys	missense_variant	Exon 6 of 7		NP_001158091.1	P51654-2Q53H15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8 link	c.1561C>T	p.Arg521Cys	missense_variant	Exon 7 of 8	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111789

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000547

AC:

AN:

182973

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1095571

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361029

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26338

American (AMR)

AF:

0.00

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19366

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40529

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839709

Other (OTH)

AF:

0.00

AC:

AN:

46014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111789

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33981

show subpopulations

African (AFR)

AF:

0.0000652

AC:

AN:

30689

American (AMR)

AF:

0.00

AC:

AN:

10553

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2651

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6065

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53192

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Simpson-Golabi-Behmel syndrome type 1;CN033288:Wilms tumor 1

Uncertain:1

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Wilms tumor 1

Benign:1

Jul 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

T;.;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.077

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.7

L;.;.

PhyloP100

5.7

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.9

N;N;.

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.42

MutPred

0.59

Gain of ubiquitination at K517 (P = 0.0754);.;.;

MVP

0.79

MPC

0.85

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.66

gMVP

0.73

Mutation Taster

=78/22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over