Genetic Variant GPC3:p.Cys498* (chrX-133596519-G-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_004484.4(GPC3):c.1494C>A(p.Cys498*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C498C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

GPC3
NM_004484.4 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -3.23

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: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-133596519-G-T is Pathogenic according to our data. Variant chrX-133596519-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 617901.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	HGVSp	Effect	Exon Rank	Protein
GPC3	NM_004484.4	MANE Select	c.1494C>A	p.Cys498*	stop_gained	Exon 7 of 8	NP_004475.1
GPC3	NM_001164617.2		c.1563C>A	p.Cys521*	stop_gained	Exon 8 of 9	NP_001158089.1
GPC3	NM_001164618.2		c.1446C>A	p.Cys482*	stop_gained	Exon 7 of 8	NP_001158090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.1494C>A	p.Cys498*	stop_gained	Exon 7 of 8	ENSP00000359854.3
GPC3	ENST00000394299.7	TSL:1	c.1563C>A	p.Cys521*	stop_gained	Exon 8 of 9	ENSP00000377836.2
GPC3	ENST00000631057.2	TSL:1	c.1332C>A	p.Cys444*	stop_gained	Exon 6 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1090733

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356553

African (AFR)

AF:

0.00

AC:

AN:

26246

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19341

East Asian (EAS)

AF:

0.00

AC:

AN:

30174

South Asian (SAS)

AF:

0.00

AC:

AN:

53964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

835319

Other (OTH)

AF:

0.00

AC:

AN:

45845

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Simpson-Golabi-Behmel syndrome type 1

Pathogenic:1

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.86

FATHMM_MKL

Benign

0.022

PhyloP100

-3.2

Vest4

0.81

ClinPred

0.60

GERP RS

-9.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=6/194

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over