rs4647609

Positions:

• chr4-184646808-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004346.4(CASP3):​c.-16+1657T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 151,714 control chromosomes in the GnomAD database, including 1,165 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1165 hom., cov: 30)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.481

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP3	NM_004346.4	c.-16+1657T>C		intron_variant		ENST00000308394.9	NP_004337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9	c.-16+1657T>C		intron_variant		1	NM_004346.4	ENSP00000311032	P1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16425 AN: 151596 Hom.: 1164 Cov.: 30

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0914

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.150

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.108 AC: 16425 AN: 151714 Hom.: 1165 Cov.: 30 AF XY: 0.109 AC XY: 8058 AN XY: 74086

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0926

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.148

Alfa AF: 0.130 Hom.: 188

Bravo AF: 0.104

Asia WGS AF: 0.0450 AC: 160 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.0
DANN	Benign	0.71

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

Other links and lift over

dbSNP: rs4647609; hg19: chr4-185567962;