chr4-184635399-C-G

Variant names:

• chr4-184635399-C-G
• NM_004346.4:c.73G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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 𝑓: 6.9e-7 (0 hom.)
• Consequence: CASP3 NM_004346.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.99

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]

ACMG classification

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
CASP3	NM_004346.4	c.73G>C	p.Glu25Gln	missense_variant	Exon 4 of 8	ENST00000308394.9	NP_004337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9	c.73G>C	p.Glu25Gln	missense_variant	Exon 4 of 8	1	NM_004346.4	ENSP00000311032.4

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

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;