X-133754151-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 2P and 18B. PM5BP4_ModerateBP6_Very_StrongBS1BS2

The NM_004484.4(GPC3):c.363T>A(p.His121Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000591 in 1,184,773 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H121Y) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000093 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000056 ( 0 hom. 2 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.253

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: Benign. The variant received -16 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-133754153-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11690.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.08580905).

BP6

Variant X-133754151-A-T is Benign according to our data. Variant chrX-133754151-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 572682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000557 (6/1077754) while in subpopulation EAS AF = 0.000199 (6/30133). AF 95% confidence interval is 0.0000862. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4 link	c.363T>A	p.His121Gln	missense_variant	Exon 3 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.363T>A	p.His121Gln	missense_variant	Exon 3 of 8	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.00000934

AC:

AN:

107019

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:

0.000290

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:

0.0000509

AC:

AN:

176714

AF XY:

0.0000477

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000662

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000557

AC:

AN:

1077754

Hom.:

Cov.:

AF XY:

0.00000579

AC XY:

AN XY:

345600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25908

American (AMR)

AF:

0.00

AC:

AN:

34822

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19178

East Asian (EAS)

AF:

0.000199

AC:

AN:

30133

South Asian (SAS)

AF:

0.00

AC:

AN:

52644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4045

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

825410

Other (OTH)

AF:

0.00

AC:

AN:

45422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00000934

AC:

AN:

107019

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29699

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29251

American (AMR)

AF:

0.00

AC:

AN:

9737

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2576

East Asian (EAS)

AF:

0.000290

AC:

AN:

3444

South Asian (SAS)

AF:

0.00

AC:

AN:

2334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

231

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51785

Other (OTH)

AF:

0.00

AC:

AN:

1423

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Sep 23, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Wilms tumor 1

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.33

T;.;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.086

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.45

N;N;.

PhyloP100

0.25

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.66

N;N;.

REVEL

Benign

0.087

Sift

Benign

0.91

T;T;.

Sift4G

Benign

0.87

T;T;T

Polyphen

0.024

B;.;.

Vest4

0.19

MutPred

0.62

Gain of ubiquitination at K123 (P = 0.0632);Gain of ubiquitination at K123 (P = 0.0632);.;

MVP

0.65

MPC

0.18

ClinPred

0.054

GERP RS

1.5

PromoterAI

0.0012

Neutral

(source)

Varity_R

0.26

gMVP

0.63

Mutation Taster

=84/16

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over