dbSNP rs61754631: GPC3:p.Ala542Ala (chrX-133536241-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004484.4(GPC3):c.1626A>G(p.Ala542Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,201,163 control chromosomes in the GnomAD database, including 837 homozygotes. There are 3,145 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 417 hom., 1428 hem., cov: 20)

Exomes 𝑓: 0.0060 ( 420 hom. 1717 hem. )

Consequence

GPC3
NM_004484.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.239

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant X-133536241-T-C is Benign according to our data. Variant chrX-133536241-T-C is described in ClinVar as Benign. ClinVar VariationId is 137490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.239 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

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.1626A>G	p.Ala542Ala	synonymous	Exon 8 of 8	NP_004475.1	I6QTG3
GPC3	NM_001164617.2		c.1695A>G	p.Ala565Ala	synonymous	Exon 9 of 9	NP_001158089.1	P51654-3
GPC3	NM_001164618.2		c.1578A>G	p.Ala526Ala	synonymous	Exon 8 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.1626A>G	p.Ala542Ala	synonymous	Exon 8 of 8	ENSP00000359854.3	P51654-1
GPC3	ENST00000394299.7	TSL:1	c.1695A>G	p.Ala565Ala	synonymous	Exon 9 of 9	ENSP00000377836.2	P51654-3
GPC3	ENST00000631057.2	TSL:1	c.1464A>G	p.Ala488Ala	synonymous	Exon 7 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes

AF:

0.0530

AC:

5803

AN:

109415

Hom.:

415

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0198

Gnomad ASJ

AF:

0.00686

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000806

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00844

Gnomad NFE

AF:

0.000607

Gnomad OTH

AF:

0.0439

GnomAD2 exomes

AF:

0.0163

AC:

2981

AN:

182961

AF XY:

0.0103

show subpopulations

Gnomad AFR exome

AF:

0.200

Gnomad AMR exome

AF:

0.00831

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000503

Gnomad OTH exome

AF:

0.00685

GnomAD4 exome

AF:

0.00601

AC:

6564

AN:

1091692

Hom.:

420

Cov.:

AF XY:

0.00481

AC XY:

1717

AN XY:

357228

show subpopulations

African (AFR)

AF:

0.197

AC:

5184

AN:

26260

American (AMR)

AF:

0.00991

AC:

349

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00672

AC:

130

AN:

19350

East Asian (EAS)

AF:

0.00

AC:

AN:

30183

South Asian (SAS)

AF:

0.000333

AC:

AN:

53996

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.0121

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.000255

AC:

213

AN:

836193

Other (OTH)

AF:

0.0135

AC:

619

AN:

45856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

228

456

684

912

1140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.0532

AC:

5819

AN:

109471

Hom.:

417

Cov.:

AF XY:

0.0449

AC XY:

1428

AN XY:

31775

show subpopulations

African (AFR)

AF:

0.184

AC:

5500

AN:

29889

American (AMR)

AF:

0.0198

AC:

202

AN:

10198

Ashkenazi Jewish (ASJ)

AF:

0.00686

AC:

AN:

2622

East Asian (EAS)

AF:

0.00

AC:

AN:

3472

South Asian (SAS)

AF:

0.000808

AC:

AN:

2475

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5690

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000607

AC:

AN:

52748

Other (OTH)

AF:

0.0433

AC:

AN:

1477

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

174

348

523

697

871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0282

Hom.:

163

Bravo

AF:

0.0613

EpiCase

AF:

0.00104

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Inborn genetic diseases (1)

Simpson-Golabi-Behmel syndrome type 1 (1)

Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

2.2

(source)

DANN

Benign

0.39

PhyloP100

0.24

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over