dbSNP rs755733724: GPC3:p.Lys123Glu (chrX-133754147-T-C) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001164617.2(GPC3):c.367A>G(p.Lys123Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,193,784 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K123N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000019 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000037 ( 0 hom. 2 hem. )

Consequence

GPC3
NM_001164617.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.28

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09209862).

BP6

Variant X-133754147-T-C is Benign according to our data. Variant chrX-133754147-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 408886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000368 (4/1087469) while in subpopulation EAS AF = 0.000133 (4/30172). AF 95% confidence interval is 0.0000449. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164617.2. 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.367A>G	p.Lys123Glu	missense	Exon 3 of 8	NP_004475.1
GPC3	NM_001164617.2		c.367A>G	p.Lys123Glu	missense	Exon 3 of 9	NP_001158089.1
GPC3	NM_001164618.2		c.319A>G	p.Lys107Glu	missense	Exon 3 of 8	NP_001158090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPC3	ENST00000370818.8	TSL:1 MANE Select	c.367A>G	p.Lys123Glu	missense	Exon 3 of 8	ENSP00000359854.3
GPC3	ENST00000394299.7	TSL:1	c.367A>G	p.Lys123Glu	missense	Exon 3 of 9	ENSP00000377836.2
GPC3	ENST00000631057.2	TSL:1	c.205A>G	p.Lys69Glu	missense	Exon 2 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes

AF:

0.0000188

AC:

AN:

106315

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:

0.000293

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000704

GnomAD2 exomes

AF:

0.0000169

AC:

AN:

177735

AF XY:

0.0000314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000220

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000368

AC:

AN:

1087469

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

353575

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26097

American (AMR)

AF:

0.00

AC:

AN:

34866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19245

East Asian (EAS)

AF:

0.000133

AC:

AN:

30172

South Asian (SAS)

AF:

0.00

AC:

AN:

52924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4088

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

834169

Other (OTH)

AF:

0.00

AC:

AN:

45690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000188

AC:

AN:

106315

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29339

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28858

American (AMR)

AF:

0.00

AC:

AN:

9743

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2578

East Asian (EAS)

AF:

0.000293

AC:

AN:

3414

South Asian (SAS)

AF:

0.00

AC:

AN:

2358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51696

Other (OTH)

AF:

0.000704

AC:

AN:

1420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.0000189

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Ovarian cancer (1)

Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.24

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.83

M_CAP

Benign

0.0071

MetaRNN

Benign

0.092

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

PhyloP100

2.3

PrimateAI

Uncertain

0.72

PROVEAN

Benign

1.2

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.015

Vest4

0.14

MutPred

0.50

Loss of ubiquitination at K123 (P = 0.0233)

MVP

0.30

MPC

0.26

ClinPred

0.049

GERP RS

5.3

PromoterAI

-0.0067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.66

Mutation Taster

=98/2

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