rs4647652

Positions:

• chr4-184637530-G-A

Variant summary

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

The NM_004346.4(CASP3):​c.53+871C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,078 control chromosomes in the GnomAD database, including 3,016 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 0.16 (3016 hom., cov: 32)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP3	NM_004346.4	c.53+871C>T		intron_variant		ENST00000308394.9	NP_004337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9	c.53+871C>T		intron_variant		1	NM_004346.4	ENSP00000311032	P1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24053 AN: 151960 Hom.: 3009 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.0920

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.139

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

GnomAD4 genome AF: 0.158 AC: 24076 AN: 152078 Hom.: 3016 Cov.: 32 AF XY: 0.169 AC XY: 12559 AN XY: 74336

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.0920

Gnomad4 EAS AF: 0.704

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.141

Alfa AF: 0.131 Hom.: 172

Bravo AF: 0.166

Asia WGS AF: 0.445 AC: 1544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.65

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: rs4647652; hg19: chr4-185558684;