Genetic Variant GPC3:p.Pro31dup (chrX-133985356-C-CCGG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_004484.4(GPC3):c.91_93dupCCG(p.Pro31dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000499 in 1,202,794 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P31P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000050 ( 0 hom. 10 hem. )

Consequence

GPC3
NM_004484.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.245

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004484.4

BP6

Variant X-133985356-C-CCGG is Benign according to our data. Variant chrX-133985356-C-CCGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408895.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000447 (5/111805) while in subpopulation NFE AF = 0.0000757 (4/52852). AF 95% confidence interval is 0.0000257. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 10 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	HGVSp	Effect	Exon Rank	Protein	UniProt
GPC3	NM_004484.4	MANE Select	c.91_93dupCCG	p.Pro31dup	conservative_inframe_insertion	Exon 1 of 8	NP_004475.1	I6QTG3
GPC3	NM_001164617.2		c.91_93dupCCG	p.Pro31dup	conservative_inframe_insertion	Exon 1 of 9	NP_001158089.1	P51654-3
GPC3	NM_001164618.2		c.91_93dupCCG	p.Pro31dup	conservative_inframe_insertion	Exon 1 of 8	NP_001158090.1	B4DTD8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.91_93dupCCG	p.Pro31dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000359854.3	P51654-1
GPC3	ENST00000394299.7	TSL:1	c.91_93dupCCG	p.Pro31dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000377836.2	P51654-3
GPC3	ENST00000631057.2	TSL:1	c.91_93dupCCG	p.Pro31dup	conservative_inframe_insertion	Exon 1 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111805

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.0000757

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000247

AC:

AN:

161907

AF XY:

0.0000187

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000570

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000504

AC:

AN:

1090989

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

357637

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26295

American (AMR)

AF:

0.00

AC:

AN:

34658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19235

East Asian (EAS)

AF:

0.0000334

AC:

AN:

29966

South Asian (SAS)

AF:

0.0000378

AC:

AN:

52894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4061

European-Non Finnish (NFE)

AF:

0.0000596

AC:

AN:

838802

Other (OTH)

AF:

0.0000219

AC:

AN:

45762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000447

AC:

AN:

111805

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34199

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30825

American (AMR)

AF:

0.00

AC:

AN:

10755

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3462

South Asian (SAS)

AF:

0.00

AC:

AN:

2743

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.0000757

AC:

AN:

52852

Other (OTH)

AF:

0.00

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.24

Mutation Taster

=71/29

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over