X-133303187-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_001448.3(GPC4):​c.1447G>A​(p.Asp483Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,097,813 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000055 ( 0 hom. 3 hem. )

Consequence

GPC4
NM_001448.3 missense

Scores

4
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
GPC4 (HGNC:4452): (glypican 4) 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 GPC4 gene is adjacent to the 3' end of GPC3 and may also play a role in Simpson-Golabi-Behmel syndrome. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.966
BS2
High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GPC4NM_001448.3 linkc.1447G>A p.Asp483Asn missense_variant Exon 8 of 9 ENST00000370828.4 NP_001439.2 O75487-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GPC4ENST00000370828.4 linkc.1447G>A p.Asp483Asn missense_variant Exon 8 of 9 1 NM_001448.3 ENSP00000359864.3 O75487-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.00000547
AC:
1
AN:
182685
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
67245
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 SAS 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:
0.00000547
AC:
6
AN:
1097813
Hom.:
0
Cov.:
30
AF XY:
0.00000826
AC XY:
3
AN XY:
363181
show subpopulations
Gnomad4 AFR exome
AF:
0.0000379
Gnomad4 AMR exome
AF:
0.0000568
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000356
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 15, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with GPC4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 483 of the GPC4 protein (p.Asp483Asn). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
23
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.38
T
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-4.3
D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.034
D
Polyphen
1.0
D
Vest4
0.81
MutPred
0.83
Loss of phosphorylation at Y479 (P = 0.1162);
MVP
0.47
MPC
1.5
ClinPred
0.93
D
GERP RS
5.6
Varity_R
0.58
gMVP
0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1245739176; hg19: chrX-132437215; API