Genetic Variant GPC3:p.Ala128Ala (chrX-133754130-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_004484.4(GPC3):c.384C>T(p.Ala128Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000498 in 1,204,923 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A128A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000054 ( 0 hom. 18 hem. )

Consequence

GPC3
NM_004484.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.40

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant X-133754130-G-A is Benign according to our data. Variant chrX-133754130-G-A is described in ClinVar as Benign. ClinVar VariationId is 543105.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000539 (59/1095578) while in subpopulation NFE AF = 0.0000702 (59/839931). AF 95% confidence interval is 0.0000553. There are 0 homozygotes in GnomAdExome4. There are 18 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 18 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
GPC3	NM_004484.4	MANE Select	c.384C>T	p.Ala128Ala	synonymous	Exon 3 of 8	NP_004475.1
GPC3	NM_001164617.2		c.384C>T	p.Ala128Ala	synonymous	Exon 3 of 9	NP_001158089.1
GPC3	NM_001164618.2		c.336C>T	p.Ala112Ala	synonymous	Exon 3 of 8	NP_001158090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.384C>T	p.Ala128Ala	synonymous	Exon 3 of 8	ENSP00000359854.3
GPC3	ENST00000394299.7	TSL:1	c.384C>T	p.Ala128Ala	synonymous	Exon 3 of 9	ENSP00000377836.2
GPC3	ENST00000631057.2	TSL:1	c.222C>T	p.Ala74Ala	synonymous	Exon 2 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes

AF:

0.00000915

AC:

AN:

109345

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000385

AC:

AN:

181583

AF XY:

0.0000449

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000869

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000539

AC:

AN:

1095578

Hom.:

Cov.:

AF XY:

0.0000499

AC XY:

AN XY:

361012

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26343

American (AMR)

AF:

0.00

AC:

AN:

35175

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19360

East Asian (EAS)

AF:

0.00

AC:

AN:

30198

South Asian (SAS)

AF:

0.00

AC:

AN:

53996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40435

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.0000702

AC:

AN:

839931

Other (OTH)

AF:

0.00

AC:

AN:

46019

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.00000915

AC:

AN:

109345

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31697

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29893

American (AMR)

AF:

0.00

AC:

AN:

10164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2622

East Asian (EAS)

AF:

0.00

AC:

AN:

3503

South Asian (SAS)

AF:

0.00

AC:

AN:

2484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52578

Other (OTH)

AF:

0.00

AC:

AN:

1458

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Wilms tumor 1

Benign:1

Apr 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.8

(source)

DANN

Benign

0.65

PhyloP100

4.4

PromoterAI

-0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over