dbSNP rs200782847: GPC3:c.1032+9C>T (chrX-133753473-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.1032+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,181,505 control chromosomes in the GnomAD database, including 3 homozygotes. There are 247 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 0.00065 ( 0 hom., 27 hem., cov: 22)

Exomes 𝑓: 0.00067 ( 3 hom. 220 hem. )

Consequence

GPC3
NM_004484.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.211

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant X-133753473-G-A is Benign according to our data. Variant chrX-133753473-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000655 (73/111474) while in subpopulation AMR AF = 0.00249 (26/10429). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 27 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	Effect	Exon Rank	Protein
GPC3	NM_004484.4	MANE Select	c.1032+9C>T	intron	N/A	NP_004475.1
GPC3	NM_001164617.2		c.1032+9C>T	intron	N/A	NP_001158089.1
GPC3	NM_001164618.2		c.984+9C>T	intron	N/A	NP_001158090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.1032+9C>T	intron	N/A	ENSP00000359854.3
GPC3	ENST00000394299.7	TSL:1	c.1032+9C>T	intron	N/A	ENSP00000377836.2
GPC3	ENST00000631057.2	TSL:1	c.870+9C>T	intron	N/A	ENSP00000486325.1

Frequencies

GnomAD3 genomes

AF:

0.000655

AC:

AN:

111474

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.0136

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00102

AC:

186

AN:

182812

AF XY:

0.000919

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000474

Gnomad ASJ exome

AF:

0.0171

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000492

Gnomad OTH exome

AF:

0.00111

GnomAD4 exome

AF:

0.000667

AC:

714

AN:

1070031

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

220

AN XY:

340823

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25887

American (AMR)

AF:

0.000426

AC:

AN:

35179

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

344

AN:

19200

East Asian (EAS)

AF:

0.00

AC:

AN:

30083

South Asian (SAS)

AF:

0.00

AC:

AN:

53498

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40497

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4066

European-Non Finnish (NFE)

AF:

0.000369

AC:

301

AN:

816404

Other (OTH)

AF:

0.00117

AC:

AN:

45217

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000655

AC:

AN:

111474

Hom.:

Cov.:

AF XY:

0.000802

AC XY:

AN XY:

33662

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30595

American (AMR)

AF:

0.00249

AC:

AN:

10429

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3564

South Asian (SAS)

AF:

0.00

AC:

AN:

2642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000188

AC:

AN:

53103

Other (OTH)

AF:

0.00

AC:

AN:

1507

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

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:

0.00373

Hom.:

Bravo

AF:

0.000756

EpiCase

AF:

0.000218

EpiControl

AF:

0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Wilms tumor 1

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Simpson-Golabi-Behmel syndrome type 1;CN033288:Wilms tumor 1

Benign:1

May 19, 2022

Fulgent Genetics, Fulgent Genetics

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

-0.84

CADD

Benign

8.7

(source)

DANN

Benign

0.60

PhyloP100

0.21

PromoterAI

-0.018

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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