chrX-133754180-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_004484.4(GPC3):c.338-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., 0 hem., cov: 18)

Exomes 𝑓: 0.000075 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

GPC3
NM_004484.4 splice_region, intron

Scores

Splicing: ADA: 0.00007847

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.447

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant X-133754180-T-A is Benign according to our data. Variant chrX-133754180-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 476654.Status of the report is criteria_provided_single_submitter, 1 stars.

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.338-4A>T	splice_region intron	N/A	NP_004475.1
GPC3	NM_001164617.2		c.338-4A>T	splice_region intron	N/A	NP_001158089.1
GPC3	NM_001164618.2		c.290-4A>T	splice_region intron	N/A	NP_001158090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.338-4A>T	splice_region intron	N/A	ENSP00000359854.3
GPC3	ENST00000394299.7	TSL:1	c.338-4A>T	splice_region intron	N/A	ENSP00000377836.2
GPC3	ENST00000631057.2	TSL:1	c.176-4A>T	splice_region intron	N/A	ENSP00000486325.1

Frequencies

GnomAD3 genomes

AF:

0.000249

AC:

AN:

76423

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000291

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:

0.000704

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000290

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000749

AC:

AN:

867494

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

254276

show subpopulations

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

African (AFR)

AF:

0.000439

AC:

AN:

20501

American (AMR)

AF:

0.0000746

AC:

AN:

26800

Ashkenazi Jewish (ASJ)

AF:

0.000176

AC:

AN:

17020

East Asian (EAS)

AF:

0.000139

AC:

AN:

28838

South Asian (SAS)

AF:

0.0000225

AC:

AN:

44357

European-Finnish (FIN)

AF:

0.000483

AC:

AN:

33116

Middle Eastern (MID)

AF:

0.000326

AC:

AN:

3070

European-Non Finnish (NFE)

AF:

0.0000366

AC:

AN:

655839

Other (OTH)

AF:

0.000132

AC:

AN:

37953

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.327

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000249

AC:

AN:

76414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

17816

show subpopulations

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

African (AFR)

AF:

0.000291

AC:

AN:

20625

American (AMR)

AF:

0.00

AC:

AN:

7247

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1944

East Asian (EAS)

AF:

0.00

AC:

AN:

2596

South Asian (SAS)

AF:

0.00

AC:

AN:

1679

European-Finnish (FIN)

AF:

0.000704

AC:

AN:

2840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

124

European-Non Finnish (NFE)

AF:

0.000290

AC:

AN:

37897

Other (OTH)

AF:

0.00

AC:

AN:

1001

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.262

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:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Wilms tumor 1

Benign:1

Jul 21, 2017

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

-0.57

CADD

Benign

6.6

(source)

DANN

Benign

0.51

PhyloP100

-0.45

PromoterAI

0.0072

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000078

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.060

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over