Genetic Variant GPC3:p.Val334Val (chrX-133753512-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004484.4(GPC3):c.1002C>T(p.Val334Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,207,791 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. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Consequence

GPC3
NM_004484.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.106

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.052).

BP6

Variant X-133753512-G-A is Benign according to our data. Variant chrX-133753512-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.106 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000639 (7/1096153) while in subpopulation EAS AF = 0.000166 (5/30197). AF 95% confidence interval is 0.0000646. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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_004484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPC3	NM_004484.4	MANE Select	c.1002C>T	p.Val334Val	synonymous	Exon 3 of 8	NP_004475.1	I6QTG3
GPC3	NM_001164617.2		c.1002C>T	p.Val334Val	synonymous	Exon 3 of 9	NP_001158089.1	P51654-3
GPC3	NM_001164618.2		c.954C>T	p.Val318Val	synonymous	Exon 3 of 8	NP_001158090.1	B4DTD8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.1002C>T	p.Val334Val	synonymous	Exon 3 of 8	ENSP00000359854.3	P51654-1
GPC3	ENST00000394299.7	TSL:1	c.1002C>T	p.Val334Val	synonymous	Exon 3 of 9	ENSP00000377836.2	P51654-3
GPC3	ENST00000631057.2	TSL:1	c.840C>T	p.Val280Val	synonymous	Exon 2 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111638

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:

0.000281

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:

0.0000164

AC:

AN:

183250

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1096153

Hom.:

Cov.:

AF XY:

0.00000830

AC XY:

AN XY:

361563

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26363

American (AMR)

AF:

0.00

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19376

East Asian (EAS)

AF:

0.000166

AC:

AN:

30197

South Asian (SAS)

AF:

0.00

AC:

AN:

54098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40527

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

840210

Other (OTH)

AF:

0.00

AC:

AN:

46041

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000179

AC:

AN:

111638

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30612

American (AMR)

AF:

0.00

AC:

AN:

10444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.000281

AC:

AN:

3556

South Asian (SAS)

AF:

0.00

AC:

AN:

2659

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6107

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53169

Other (OTH)

AF:

0.00

AC:

AN:

1511

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

Age Distribution

Genome Het

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:

0.0000227

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

5.4

(source)

DANN

Benign

0.66

PhyloP100

0.11

PromoterAI

-0.010

Neutral

(source)

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over