rs753020197

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004484.4(GPC3):​c.955G>A​(p.Val319Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,095,481 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000082 ( 0 hom. 4 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

2
1
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 3.15

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17564827).
BP6
Variant X-133753559-C-T is Benign according to our data. Variant chrX-133753559-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476670.
BS2
High Hemizygotes in GnomAdExome4 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

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GPC3
NM_004484.4
MANE Select
c.955G>Ap.Val319Ile
missense
Exon 3 of 8NP_004475.1I6QTG3
GPC3
NM_001164617.2
c.955G>Ap.Val319Ile
missense
Exon 3 of 9NP_001158089.1P51654-3
GPC3
NM_001164618.2
c.907G>Ap.Val303Ile
missense
Exon 3 of 8NP_001158090.1B4DTD8

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GPC3
ENST00000370818.8
TSL:1 MANE Select
c.955G>Ap.Val319Ile
missense
Exon 3 of 8ENSP00000359854.3P51654-1
GPC3
ENST00000394299.7
TSL:1
c.955G>Ap.Val319Ile
missense
Exon 3 of 9ENSP00000377836.2P51654-3
GPC3
ENST00000631057.2
TSL:1
c.793G>Ap.Val265Ile
missense
Exon 2 of 7ENSP00000486325.1P51654-2

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD2 exomes
AF:
0.00000546
AC:
1
AN:
183303
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000365
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:
0.00000822
AC:
9
AN:
1095481
Hom.:
0
Cov.:
31
AF XY:
0.0000111
AC XY:
4
AN XY:
360885
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26350
American (AMR)
AF:
0.0000284
AC:
1
AN:
35204
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19368
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30194
South Asian (SAS)
AF:
0.0000185
AC:
1
AN:
54084
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40531
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4126
European-Non Finnish (NFE)
AF:
0.00000834
AC:
7
AN:
839618
Other (OTH)
AF:
0.00
AC:
0
AN:
46006
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.405
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<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
Cov.:
23
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

ClinVar submissions
Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
-
Inborn genetic diseases (1)
-
-
1
not provided (1)
-
1
-
not specified (1)
-
1
-
Simpson-Golabi-Behmel syndrome type 1;CN033288:Wilms tumor 1 (1)
-
-
1
Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
14
DANN
Benign
0.97
DEOGEN2
Uncertain
0.48
T
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.72
T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
2.0
M
PhyloP100
3.1
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.89
N
REVEL
Benign
0.091
Sift
Benign
0.16
T
Sift4G
Pathogenic
0.0
D
Polyphen
0.030
B
Vest4
0.14
MutPred
0.54
Gain of helix (P = 0.2059)
MVP
0.30
MPC
0.16
ClinPred
0.14
T
GERP RS
2.7
PromoterAI
0.00010
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.096
gMVP
0.58
Mutation Taster
=83/17
polymorphism

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

Other links and lift over

dbSNP: rs753020197; hg19: chrX-132887586; API
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.