dbSNP rs375606908: GPC3:p.Pro544Leu (chrX-133536236-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004484.4(GPC3):c.1631C>T(p.Pro544Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,199,749 control chromosomes in the GnomAD database, including 1 homozygotes. There are 62 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 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. P544R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 1 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.00016 ( 0 hom. 58 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.464

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

GPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008171827).

BP6

Variant X-133536236-G-A is Benign according to our data. Variant chrX-133536236-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000128 (14/109594) while in subpopulation EAS AF = 0.00404 (14/3467). AF 95% confidence interval is 0.00244. There are 1 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 4 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.1631C>T	p.Pro544Leu	missense	Exon 8 of 8	NP_004475.1	I6QTG3
GPC3	NM_001164617.2		c.1700C>T	p.Pro567Leu	missense	Exon 9 of 9	NP_001158089.1	P51654-3
GPC3	NM_001164618.2		c.1583C>T	p.Pro528Leu	missense	Exon 8 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.1631C>T	p.Pro544Leu	missense	Exon 8 of 8	ENSP00000359854.3	P51654-1
GPC3	ENST00000394299.7	TSL:1	c.1700C>T	p.Pro567Leu	missense	Exon 9 of 9	ENSP00000377836.2	P51654-3
GPC3	ENST00000631057.2	TSL:1	c.1469C>T	p.Pro490Leu	missense	Exon 7 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes

AF:

0.000128

AC:

AN:

109536

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:

0.00403

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:

0.000317

AC:

AN:

182945

AF XY:

0.000326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00404

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000157

AC:

171

AN:

1090155

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

355779

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26219

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19339

East Asian (EAS)

AF:

0.00457

AC:

138

AN:

30178

South Asian (SAS)

AF:

0.0000185

AC:

AN:

53963

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

834807

Other (OTH)

AF:

0.000240

AC:

AN:

45812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000128

AC:

AN:

109594

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

31866

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30073

American (AMR)

AF:

0.00

AC:

AN:

10164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2628

East Asian (EAS)

AF:

0.00404

AC:

AN:

3467

South Asian (SAS)

AF:

0.00

AC:

AN:

2469

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52718

Other (OTH)

AF:

0.00

AC:

AN:

1480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.000305

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Simpson-Golabi-Behmel syndrome type 1 (1)

Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.31

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.83

M_CAP

Benign

0.021

MetaRNN

Benign

0.0082

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

0.46

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.91

REVEL

Benign

0.033

Sift

Benign

0.16

Sift4G

Benign

0.15

Polyphen

0.050

Vest4

0.15

MutPred

0.57

Loss of loop (P = 0.0128)

MVP

0.24

MPC

0.18

ClinPred

0.020

GERP RS

-0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.045

gMVP

0.26

Mutation Taster

=99/1

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over