X-133661837-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BS1BS2

The NM_001164617.2(GPC3):c.1375G>A(p.Ala459Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,086,642 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. A459S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.0000028 ( 0 hom. 3 hem. )

Consequence

GPC3
NM_001164617.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.60

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30018583).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000276 (3/1086642) while in subpopulation EAS AF = 0.0000996 (3/30109). AF 95% confidence interval is 0.0000264. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164617.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPC3	NM_004484.4	MANE Select	c.1306G>A	p.Ala436Thr	missense	Exon 6 of 8	NP_004475.1
GPC3	NM_001164617.2		c.1375G>A	p.Ala459Thr	missense	Exon 7 of 9	NP_001158089.1
GPC3	NM_001164618.2		c.1258G>A	p.Ala420Thr	missense	Exon 6 of 8	NP_001158090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.1306G>A	p.Ala436Thr	missense	Exon 6 of 8	ENSP00000359854.3
GPC3	ENST00000394299.7	TSL:1	c.1375G>A	p.Ala459Thr	missense	Exon 7 of 9	ENSP00000377836.2
GPC3	ENST00000631057.2	TSL:1	c.1144G>A	p.Ala382Thr	missense	Exon 5 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1086642

Hom.:

Cov.:

AF XY:

0.00000851

AC XY:

AN XY:

352560

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26199

American (AMR)

AF:

0.00

AC:

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19277

East Asian (EAS)

AF:

0.0000996

AC:

AN:

30109

South Asian (SAS)

AF:

0.00

AC:

AN:

53899

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40401

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4101

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

831794

Other (OTH)

AF:

0.00

AC:

AN:

45690

Age Distribution

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.6

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.35

REVEL

Benign

0.085

Sift

Benign

0.067

Sift4G

Benign

0.14

Polyphen

0.41

Vest4

0.27

MutPred

0.77

Loss of ubiquitination at K435 (P = 0.0618)

MVP

0.33

MPC

0.21

ClinPred

0.53

GERP RS

4.2

Varity_R

0.096

gMVP

0.34

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over