Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_004484.4(GPC3):c.1114G>A(p.Val372Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000493 in 1,197,481 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000053 ( 0 hom. 13 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.23

Publications

2 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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10329887).

BP6

Variant X-133699947-C-T is Benign according to our data. Variant chrX-133699947-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476640.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000525 (57/1085402) while in subpopulation NFE AF = 0.000065 (54/831122). AF 95% confidence interval is 0.0000509. There are 0 homozygotes in GnomAdExome4. There are 13 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 13 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
GPC3	NM_004484.4	MANE Select	c.1114G>A	p.Val372Ile	missense	Exon 4 of 8	NP_004475.1
GPC3	NM_001164617.2		c.1183G>A	p.Val395Ile	missense	Exon 5 of 9	NP_001158089.1
GPC3	NM_001164618.2		c.1066G>A	p.Val356Ile	missense	Exon 4 of 8	NP_001158090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.1114G>A	p.Val372Ile	missense	Exon 4 of 8	ENSP00000359854.3
GPC3	ENST00000394299.7	TSL:1	c.1183G>A	p.Val395Ile	missense	Exon 5 of 9	ENSP00000377836.2
GPC3	ENST00000631057.2	TSL:1	c.952G>A	p.Val318Ile	missense	Exon 3 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112079

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000496

AC:

AN:

181332

AF XY:

0.0000151

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:

0.000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000525

AC:

AN:

1085402

Hom.:

Cov.:

AF XY:

0.0000370

AC XY:

AN XY:

351342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26159

American (AMR)

AF:

0.00

AC:

AN:

35081

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19278

East Asian (EAS)

AF:

0.00

AC:

AN:

30109

South Asian (SAS)

AF:

0.00

AC:

AN:

53442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40499

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4043

European-Non Finnish (NFE)

AF:

0.0000650

AC:

AN:

831122

Other (OTH)

AF:

0.0000657

AC:

AN:

45669

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

112079

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34253

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30857

American (AMR)

AF:

0.00

AC:

AN:

10600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3571

South Asian (SAS)

AF:

0.00

AC:

AN:

2696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6037

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53227

Other (OTH)

AF:

0.00

AC:

AN:

1510

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 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:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

M_CAP

Benign

0.0054

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

2.2

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.58

REVEL

Benign

0.080

Sift

Benign

0.44

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.18

MVP

0.36

MPC

0.14

ClinPred

0.085

GERP RS

2.5

Varity_R

0.045

gMVP

0.14

Mutation Taster

=97/3

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.

rs140756498

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over