X-133754180-TAAAAAA-TAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_004484.4(GPC3):c.338-6_338-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000065 ( 0 hom., 1 hem., cov: 19)

Exomes 𝑓: 0.0024 ( 0 hom. 0 hem. )

Consequence

GPC3
NM_004484.4 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

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 -12 ACMG points.

BP6

Variant X-133754180-T-TAA is Benign according to our data. Variant chrX-133754180-T-TAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1692814.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 = 0.0000654 (5/76495) while in subpopulation AFR AF = 0.000146 (3/20618). AF 95% confidence interval is 0.0000395. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4 link	c.338-6_338-5dupTT		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_338-4insTT		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0000654

AC:

AN:

76495

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000146

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:

0.0000527

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00310

AC:

224

AN:

72176

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00554

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.00534

Gnomad EAS exome

AF:

0.00314

Gnomad FIN exome

AF:

0.00383

Gnomad NFE exome

AF:

0.00242

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00240

AC:

2057

AN:

858102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

249560

show subpopulations

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

African (AFR)

AF:

0.00291

AC:

AN:

20258

American (AMR)

AF:

0.000789

AC:

AN:

26600

Ashkenazi Jewish (ASJ)

AF:

0.00244

AC:

AN:

16834

East Asian (EAS)

AF:

0.000838

AC:

AN:

28647

South Asian (SAS)

AF:

0.00138

AC:

AN:

43480

European-Finnish (FIN)

AF:

0.000972

AC:

AN:

32906

Middle Eastern (MID)

AF:

0.00262

AC:

AN:

3049

European-Non Finnish (NFE)

AF:

0.00269

AC:

1747

AN:

648753

Other (OTH)

AF:

0.00173

AC:

AN:

37575

⚠️ 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: 0.265

Heterozygous variant carriers

228

455

683

910

1138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

176

264

352

440

<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:

0.0000654

AC:

AN:

76495

Hom.:

Cov.:

AF XY:

0.0000560

AC XY:

AN XY:

17847

show subpopulations

African (AFR)

AF:

0.000146

AC:

AN:

20618

American (AMR)

AF:

0.00

AC:

AN:

7242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1948

East Asian (EAS)

AF:

0.00

AC:

AN:

2611

South Asian (SAS)

AF:

0.00

AC:

AN:

1693

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2839

Middle Eastern (MID)

AF:

0.00

AC:

AN:

142

European-Non Finnish (NFE)

AF:

0.0000527

AC:

AN:

37949

Other (OTH)

AF:

0.00

AC:

AN:

991

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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:

0.00262

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GPC3-related disorder

Benign:1

Aug 09, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Jul 21, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

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

Benign:1

Dec 06, 2021

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

=98/2

polymorphism

(source)

Splicing

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