chrX-133692406-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The ENST00000370818.8(GPC3):c.1255G>A(p.Asp419Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,521 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D419G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

GPC3
ENST00000370818.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.62

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3721846).

BP6

Variant X-133692406-C-T is Benign according to our data. Variant chrX-133692406-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572037.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370818.8. 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.1255G>A	p.Asp419Asn	missense	Exon 5 of 8	NP_004475.1
GPC3	NM_001164617.2		c.1324G>A	p.Asp442Asn	missense	Exon 6 of 9	NP_001158089.1
GPC3	NM_001164618.2		c.1207G>A	p.Asp403Asn	missense	Exon 5 of 8	NP_001158090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.1255G>A	p.Asp419Asn	missense	Exon 5 of 8	ENSP00000359854.3
GPC3	ENST00000394299.7	TSL:1	c.1324G>A	p.Asp442Asn	missense	Exon 6 of 9	ENSP00000377836.2
GPC3	ENST00000631057.2	TSL:1	c.1093G>A	p.Asp365Asn	missense	Exon 4 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes

AF:

0.00000885

AC:

AN:

112994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000321

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

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183386

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.0000760

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1096475

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361867

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26371

American (AMR)

AF:

0.00

AC:

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

840543

Other (OTH)

AF:

0.00

AC:

AN:

46049

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00000885

AC:

AN:

113046

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

35208

show subpopulations

African (AFR)

AF:

0.0000321

AC:

AN:

31189

American (AMR)

AF:

0.00

AC:

AN:

10729

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3598

South Asian (SAS)

AF:

0.00

AC:

AN:

2778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6267

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53379

Other (OTH)

AF:

0.00

AC:

AN:

1544

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.86

M_CAP

Benign

0.011

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.8

PhyloP100

1.6

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.67

REVEL

Benign

0.17

Sift

Benign

0.26

Sift4G

Benign

0.33

Polyphen

0.89

Vest4

0.37

MutPred

0.87

Loss of loop (P = 0.3664)

MVP

0.52

MPC

0.21

ClinPred

0.20

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.36

Mutation Taster

=86/14

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

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over