dbSNP rs587778392: GPC3:p.Arg120Cys (chrX-133754156-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004484.4(GPC3):c.358C>T(p.Arg120Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000212 in 1,156,281 control chromosomes in the GnomAD database, including 1 homozygotes. There are 117 hemizygotes in GnomAD. In-silico tool predicts 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. R120L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.00022 ( 1 hom. 113 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 4.23

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0249646).

BP6

Variant X-133754156-G-A is Benign according to our data. Variant chrX-133754156-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134500.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 = 0.000119 (12/101245) while in subpopulation EAS AF = 0.00151 (5/3309). AF 95% confidence interval is 0.000595. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 4 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.358C>T	p.Arg120Cys	missense	Exon 3 of 8	NP_004475.1	I6QTG3
GPC3	NM_001164617.2		c.358C>T	p.Arg120Cys	missense	Exon 3 of 9	NP_001158089.1	P51654-3
GPC3	NM_001164618.2		c.310C>T	p.Arg104Cys	missense	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.358C>T	p.Arg120Cys	missense	Exon 3 of 8	ENSP00000359854.3	P51654-1
GPC3	ENST00000394299.7	TSL:1	c.358C>T	p.Arg120Cys	missense	Exon 3 of 9	ENSP00000377836.2	P51654-3
GPC3	ENST00000631057.2	TSL:1	c.196C>T	p.Arg66Cys	missense	Exon 2 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

101223

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000224

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00151

Gnomad SAS

AF:

0.00137

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000398

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000391

AC:

AN:

168803

AF XY:

0.000475

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00224

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000397

Gnomad OTH exome

AF:

0.000245

GnomAD4 exome

AF:

0.000221

AC:

233

AN:

1055036

Hom.:

Cov.:

AF XY:

0.000341

AC XY:

113

AN XY:

331130

show subpopulations

African (AFR)

AF:

0.0000399

AC:

AN:

25041

American (AMR)

AF:

0.00

AC:

AN:

33196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18607

East Asian (EAS)

AF:

0.00130

AC:

AN:

29187

South Asian (SAS)

AF:

0.00298

AC:

146

AN:

48943

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39622

Middle Eastern (MID)

AF:

0.00101

AC:

AN:

3954

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

812031

Other (OTH)

AF:

0.000180

AC:

AN:

44455

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000119

AC:

AN:

101245

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

26275

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27353

American (AMR)

AF:

0.000224

AC:

AN:

8931

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2524

East Asian (EAS)

AF:

0.00151

AC:

AN:

3309

South Asian (SAS)

AF:

0.00138

AC:

AN:

2177

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

193

European-Non Finnish (NFE)

AF:

0.0000398

AC:

AN:

50288

Other (OTH)

AF:

0.00

AC:

AN:

1339

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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.:

ExAC

AF:

0.000428

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

GPC3-related disorder (1)

Hereditary cancer-predisposing syndrome (1)

Inborn genetic diseases (1)

Simpson-Golabi-Behmel syndrome type 1 (1)

Wilms tumor 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.073

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.0

PhyloP100

4.2

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.51

MVP

0.65

MPC

0.67

ClinPred

0.11

GERP RS

5.3

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.74

gMVP

0.77

Mutation Taster

=54/46

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