Genetic Variant GPC3:p.Pro363Thr (chrX-133699974-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004484.4(GPC3):c.1087C>A(p.Pro363Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000894 in 111,829 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P363R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.09

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29470292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4 link	c.1087C>A	p.Pro363Thr	missense_variant	Exon 4 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.1087C>A	p.Pro363Thr	missense_variant	Exon 4 of 8	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111829

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1076425

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

344133

African (AFR)

AF:

0.00

AC:

AN:

25999

American (AMR)

AF:

0.00

AC:

AN:

34907

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19194

East Asian (EAS)

AF:

0.00

AC:

AN:

30070

South Asian (SAS)

AF:

0.00

AC:

AN:

52843

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40491

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4016

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

823525

Other (OTH)

AF:

0.00

AC:

AN:

45380

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111829

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34043

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30785

American (AMR)

AF:

0.00

AC:

AN:

10553

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3555

South Asian (SAS)

AF:

0.00

AC:

AN:

2668

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53146

Other (OTH)

AF:

0.00

AC:

AN:

1504

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:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

T;.;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

5.1

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.52

N;N;.

REVEL

Benign

0.17

Sift

Benign

0.12

T;T;.

Sift4G

Benign

0.20

T;T;T

Polyphen

0.26

B;.;.

Vest4

0.46

MutPred

0.44

Gain of phosphorylation at P363 (P = 0.0502);.;.;

MVP

0.61

MPC

0.27

ClinPred

0.50

GERP RS

5.3

Varity_R

0.18

gMVP

0.51

Mutation Taster

=88/12

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over