rs745968470

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_004484.4(GPC3):c.1398G>A(p.Leu466Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,167,550 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000029 ( 0 hom., 2 hem., cov: 19)

Exomes 𝑓: 0.000027 ( 0 hom. 11 hem. )

Consequence

GPC3
NM_004484.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.13

Publications

2 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.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant X-133661745-C-T is Benign according to our data. Variant chrX-133661745-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198173.

BP7

Synonymous conserved (PhyloP=3.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000273 (29/1062939) while in subpopulation NFE AF = 0.0000332 (27/812304). AF 95% confidence interval is 0.0000228. There are 0 homozygotes in GnomAdExome4. There are 11 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4 link	c.1398G>A	p.Leu466Leu	synonymous_variant	Exon 6 of 8	ENST00000370818.8	NP_004475.1	P51654-1Q53H15I6QTG3
GPC3	NM_001164617.2 link	c.1467G>A	p.Leu489Leu	synonymous_variant	Exon 7 of 9		NP_001158089.1	P51654-3Q53H15
GPC3	NM_001164618.2 link	c.1350G>A	p.Leu450Leu	synonymous_variant	Exon 6 of 8		NP_001158090.1	Q53H15B4DTD8
GPC3	NM_001164619.2 link	c.1236G>A	p.Leu412Leu	synonymous_variant	Exon 5 of 7		NP_001158091.1	P51654-2Q53H15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8 link	c.1398G>A	p.Leu466Leu	synonymous_variant	Exon 6 of 8	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0000287

AC:

AN:

104611

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000584

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

183046

AF XY:

0.0000296

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:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1062939

Hom.:

Cov.:

AF XY:

0.0000329

AC XY:

AN XY:

334147

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25736

American (AMR)

AF:

0.00

AC:

AN:

34882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18875

East Asian (EAS)

AF:

0.00

AC:

AN:

29490

South Asian (SAS)

AF:

0.0000187

AC:

AN:

53348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4031

European-Non Finnish (NFE)

AF:

0.0000332

AC:

AN:

812304

Other (OTH)

AF:

0.0000224

AC:

AN:

44635

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.0000287

AC:

AN:

104611

Hom.:

Cov.:

AF XY:

0.0000727

AC XY:

AN XY:

27511

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28567

American (AMR)

AF:

0.00

AC:

AN:

9419

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2563

East Asian (EAS)

AF:

0.00

AC:

AN:

3274

South Asian (SAS)

AF:

0.00

AC:

AN:

2143

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

227

European-Non Finnish (NFE)

AF:

0.0000584

AC:

AN:

51326

Other (OTH)

AF:

0.00

AC:

AN:

1369

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000533

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 04, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Wilms tumor 1

Benign:1

Nov 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

3.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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