dbSNP rs781232455: GPC3:p.Pro31Pro (chrX-133985357-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_004484.4(GPC3):c.93G>A(p.Pro31Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,171,753 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.00013 ( 0 hom. 38 hem. )

Consequence

GPC3
NM_004484.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.245

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant X-133985357-C-T is Benign according to our data. Variant chrX-133985357-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 408892.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.245 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000628 (7/111522) while in subpopulation NFE AF = 0.000114 (6/52745). AF 95% confidence interval is 0.0000488. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 38 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.93G>A	p.Pro31Pro	synonymous	Exon 1 of 8	NP_004475.1
GPC3	NM_001164617.2		c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 9	NP_001158089.1
GPC3	NM_001164618.2		c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 8	NP_001158090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 8	ENSP00000359854.3
GPC3	ENST00000394299.7	TSL:1	c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 9	ENSP00000377836.2
GPC3	ENST00000631057.2	TSL:1	c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes

AF:

0.0000628

AC:

AN:

111522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.000114

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000383

AC:

AN:

156782

AF XY:

0.0000199

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:

0.0000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000133

AC:

141

AN:

1060231

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

335801

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25507

American (AMR)

AF:

0.00

AC:

AN:

33074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18641

East Asian (EAS)

AF:

0.0000345

AC:

AN:

28956

South Asian (SAS)

AF:

0.00

AC:

AN:

50812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3952

European-Non Finnish (NFE)

AF:

0.000168

AC:

137

AN:

816381

Other (OTH)

AF:

0.0000675

AC:

AN:

44472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.0000628

AC:

AN:

111522

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34030

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30750

American (AMR)

AF:

0.00

AC:

AN:

10730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2631

East Asian (EAS)

AF:

0.00

AC:

AN:

3460

South Asian (SAS)

AF:

0.00

AC:

AN:

2719

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6089

Middle Eastern (MID)

AF:

0.00

AC:

AN:

229

European-Non Finnish (NFE)

AF:

0.000114

AC:

AN:

52745

Other (OTH)

AF:

0.00

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.0000712

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Wilms tumor 1

Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.35

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.24

PromoterAI

-0.071

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over