X-133754180-T-TA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_004484.4(GPC3):c.338-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 23 hom., 186 hem., cov: 19)

Exomes 𝑓: 0.076 ( 1 hom. 18 hem. )

Consequence

GPC3
NM_004484.4 splice_region, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: -0.883

Publications

7 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 -16 ACMG points.

BP6

Variant X-133754180-T-TA is Benign according to our data. Variant chrX-133754180-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 695314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0171 (1305/76406) while in subpopulation AFR AF = 0.0461 (951/20630). AF 95% confidence interval is 0.0437. There are 23 homozygotes in GnomAd4. There are 186 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4 link	c.338-5dupT		splice_region_variant, intron_variant	Intron 2 of 7	ENST00000370818.8	NP_004475.1	P51654-1Q53H15I6QTG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8 link	c.338-5_338-4insT		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

1308

AN:

76415

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0463

Gnomad AMI

AF:

0.00866

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.00257

Gnomad EAS

AF:

0.00345

Gnomad SAS

AF:

0.00177

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00704

Gnomad NFE

AF:

0.00667

Gnomad OTH

AF:

0.0121

GnomAD2 exomes

AF:

0.0845

AC:

6102

AN:

72176

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.116

Gnomad AMR exome

AF:

0.0557

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.103

Gnomad FIN exome

AF:

0.0788

Gnomad NFE exome

AF:

0.0806

Gnomad OTH exome

AF:

0.0918

GnomAD4 exome

AF:

0.0761

AC:

59912

AN:

787248

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

195282

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0929

AC:

1733

AN:

18655

American (AMR)

AF:

0.0381

AC:

951

AN:

24986

Ashkenazi Jewish (ASJ)

AF:

0.0668

AC:

1010

AN:

15120

East Asian (EAS)

AF:

0.0562

AC:

1429

AN:

25423

South Asian (SAS)

AF:

0.0514

AC:

1908

AN:

37129

European-Finnish (FIN)

AF:

0.0524

AC:

1563

AN:

29842

Middle Eastern (MID)

AF:

0.0506

AC:

142

AN:

2804

European-Non Finnish (NFE)

AF:

0.0813

AC:

48682

AN:

598847

Other (OTH)

AF:

0.0724

AC:

2494

AN:

34442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.304

Heterozygous variant carriers

4392

8785

13177

17570

21962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2076

4152

6228

8304

10380

<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:

0.0171

AC:

1305

AN:

76406

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

186

AN XY:

17820

show subpopulations

African (AFR)

AF:

0.0461

AC:

951

AN:

20630

American (AMR)

AF:

0.00497

AC:

AN:

7245

Ashkenazi Jewish (ASJ)

AF:

0.00257

AC:

AN:

1946

East Asian (EAS)

AF:

0.00308

AC:

AN:

2597

South Asian (SAS)

AF:

0.00179

AC:

AN:

1679

European-Finnish (FIN)

AF:

0.0110

AC:

AN:

2824

Middle Eastern (MID)

AF:

0.00806

AC:

AN:

124

European-Non Finnish (NFE)

AF:

0.00668

AC:

253

AN:

37899

Other (OTH)

AF:

0.0130

AC:

AN:

1000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

139

186

232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0332

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Feb 24, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Wilms tumor 1

Benign:1

Dec 31, 2019

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

Jan 06, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.88

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over