Genetic Variant GPC3:p.Met476Val (chrX-133596587-T-C) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_004484.4(GPC3):c.1426A>G(p.Met476Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000215 in 1,209,296 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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. M476L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. 6 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.60

Publications

1 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0813044).

BP6

Variant X-133596587-T-C is Benign according to our data. Variant chrX-133596587-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 543108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000537 (6/111736) while in subpopulation EAS AF = 0.00084 (3/3572). AF 95% confidence interval is 0.000228. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 6 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.1426A>G	p.Met476Val	missense	Exon 7 of 8	NP_004475.1	I6QTG3
GPC3	NM_001164617.2		c.1495A>G	p.Met499Val	missense	Exon 8 of 9	NP_001158089.1	P51654-3
GPC3	NM_001164618.2		c.1378A>G	p.Met460Val	missense	Exon 7 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.1426A>G	p.Met476Val	missense	Exon 7 of 8	ENSP00000359854.3	P51654-1
GPC3	ENST00000394299.7	TSL:1	c.1495A>G	p.Met499Val	missense	Exon 8 of 9	ENSP00000377836.2	P51654-3
GPC3	ENST00000631057.2	TSL:1	c.1264A>G	p.Met422Val	missense	Exon 6 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes

AF:

0.0000537

AC:

AN:

111683

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000953

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000837

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.000665

GnomAD2 exomes

AF:

0.0000655

AC:

AN:

183341

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000649

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1097560

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

362928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26387

American (AMR)

AF:

0.000114

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19376

East Asian (EAS)

AF:

0.000464

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841517

Other (OTH)

AF:

0.0000434

AC:

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.0000537

AC:

AN:

111736

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33886

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30755

American (AMR)

AF:

0.0000952

AC:

AN:

10509

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.000840

AC:

AN:

3572

South Asian (SAS)

AF:

0.00

AC:

AN:

2576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6055

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53204

Other (OTH)

AF:

0.000657

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.000535

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000988

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

M_CAP

Benign

0.014

MetaRNN

Benign

0.081

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

4.6

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.78

REVEL

Benign

0.23

Sift

Benign

0.81

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.51

MutPred

0.36

Loss of ubiquitination at K480 (P = 0.0554)

MVP

0.95

MPC

0.18

ClinPred

0.042

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.36

Mutation Taster

=93/7

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over