rs1015207544

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004484.4(GPC3):c.1568T>C(p.Leu523Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000663 in 1,206,276 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.34

Publications

0 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 -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4 link	c.1568T>C	p.Leu523Pro	missense_variant	Exon 7 of 8	ENST00000370818.8	NP_004475.1	P51654-1Q53H15I6QTG3
GPC3	NM_001164617.2 link	c.1637T>C	p.Leu546Pro	missense_variant	Exon 8 of 9		NP_001158089.1	P51654-3Q53H15
GPC3	NM_001164618.2 link	c.1520T>C	p.Leu507Pro	missense_variant	Exon 7 of 8		NP_001158090.1	Q53H15B4DTD8
GPC3	NM_001164619.2 link	c.1406T>C	p.Leu469Pro	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.1568T>C	p.Leu523Pro	missense_variant	Exon 7 of 8	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112057

Hom.:

Cov.:

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:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1094219

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

359731

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26308

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19359

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.00

AC:

AN:

54056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4123

European-Non Finnish (NFE)

AF:

0.00000716

AC:

AN:

838492

Other (OTH)

AF:

0.00

AC:

AN:

45953

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

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:

0.0000178

AC:

AN:

112057

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

34215

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30771

American (AMR)

AF:

0.00

AC:

AN:

10575

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2669

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6127

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53268

Other (OTH)

AF:

0.00

AC:

AN:

1510

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilms tumor 1

Uncertain:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 523 of the GPC3 protein (p.Leu523Pro). This variant is present in population databases (no rsID available, gnomAD 0.009%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with GPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 543089). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Feb 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;.;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.083

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.5

L;.;.

PhyloP100

5.3

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.4

N;N;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.0030

D;D;.

Sift4G

Uncertain

0.039

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.56

MutPred

0.84

Loss of helix (P = 0.0017);.;.;

MVP

0.87

MPC

0.93

ClinPred

0.97

GERP RS

4.6

Varity_R

0.82

gMVP

0.73

Mutation Taster

=80/20

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over