chr4-184635399-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004346.4(CASP3):​c.73G>C​(p.Glu25Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E25K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

CASP3
NM_004346.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.99
Variant links:
Genes affected
CASP3 (HGNC:1504): (caspase 3) The protein encoded by this gene is a cysteine-aspartic acid protease that plays a central role in the execution-phase of cell apoptosis. The encoded protein cleaves and inactivates poly(ADP-ribose) polymerase while it cleaves and activates sterol regulatory element binding proteins as well as caspases 6, 7, and 9. This protein itself is processed by caspases 8, 9, and 10. It is the predominant caspase involved in the cleavage of amyloid-beta 4A precursor protein, which is associated with neuronal death in Alzheimer's disease. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06554699).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASP3NM_004346.4 linkc.73G>C p.Glu25Gln missense_variant Exon 4 of 8 ENST00000308394.9 NP_004337.2 P42574

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CASP3ENST00000308394.9 linkc.73G>C p.Glu25Gln missense_variant Exon 4 of 8 1 NM_004346.4 ENSP00000311032.4 P42574

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459466
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
726196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
9.01e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
18
DANN
Benign
0.86
DEOGEN2
Benign
0.17
.;T;T;.;.;T
Eigen
Benign
-0.90
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.19
.;.;T;.;T;T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.066
T;T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.0
.;N;N;.;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.010
N;N;N;N;N;N
REVEL
Benign
0.082
Sift
Benign
0.26
T;T;T;T;T;T
Sift4G
Benign
0.45
T;T;T;T;T;.
Polyphen
0.0020
B;B;B;B;B;.
Vest4
0.10
MutPred
0.19
Gain of glycosylation at S26 (P = 0.0126);Gain of glycosylation at S26 (P = 0.0126);Gain of glycosylation at S26 (P = 0.0126);Gain of glycosylation at S26 (P = 0.0126);Gain of glycosylation at S26 (P = 0.0126);Gain of glycosylation at S26 (P = 0.0126);
MVP
0.47
MPC
0.60
ClinPred
0.15
T
GERP RS
4.7
Varity_R
0.054
gMVP
0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-185556553; API