NM_004484.4:c.569C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_004484.4(GPC3):c.569C>T(p.Ser190Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,056 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S190S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.94

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05033192).

BP6

Variant X-133753945-G-A is Benign according to our data. Variant chrX-133753945-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 543085.

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.569C>T	p.Ser190Leu	missense	Exon 3 of 8	NP_004475.1	I6QTG3
GPC3	NM_001164617.2		c.569C>T	p.Ser190Leu	missense	Exon 3 of 9	NP_001158089.1	P51654-3
GPC3	NM_001164618.2		c.521C>T	p.Ser174Leu	missense	Exon 3 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.569C>T	p.Ser190Leu	missense	Exon 3 of 8	ENSP00000359854.3	P51654-1
GPC3	ENST00000394299.7	TSL:1	c.569C>T	p.Ser190Leu	missense	Exon 3 of 9	ENSP00000377836.2	P51654-3
GPC3	ENST00000631057.2	TSL:1	c.407C>T	p.Ser136Leu	missense	Exon 2 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000650

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

182455

AF XY:

0.0000446

show subpopulations

Gnomad AFR exome

AF:

0.000228

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097122

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362500

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26382

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19379

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841107

Other (OTH)

AF:

0.0000217

AC:

AN:

46062

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

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:

0.0000179

AC:

AN:

111934

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34104

show subpopulations

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

African (AFR)

AF:

0.0000650

AC:

AN:

30788

American (AMR)

AF:

0.00

AC:

AN:

10568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2660

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6083

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53190

Other (OTH)

AF:

0.00

AC:

AN:

1514

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

GPC3-related disorder (1)

Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.24

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.52

PhyloP100

1.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.020

REVEL

Benign

0.090

Sift

Benign

1.0

Sift4G

Benign

0.67

Polyphen

0.0

Vest4

0.20

MVP

0.31

MPC

0.16

ClinPred

0.019

GERP RS

4.5

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.12

gMVP

0.28

Mutation Taster

=100/0

polymorphism

(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

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

Computational scores

Splicing

Publications

Other links and lift over