rs4647601

Positions:

• chr4-184648878-C-A

Variant summary

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

The NM_004346.4(CASP3):​c.-182-247G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,078 control chromosomes in the GnomAD database, including 11,109 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 0.35 (11109 hom., cov: 33)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.635

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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP3	NM_004346.4	c.-182-247G>T		intron_variant		ENST00000308394.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP3	ENST00000308394.9	c.-182-247G>T		intron_variant		1	NM_004346.4	P1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53016 AN: 151958 Hom.: 11108 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.379

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

GnomAD4 genome AF: 0.349 AC: 53024 AN: 152078 Hom.: 11109 Cov.: 33 AF XY: 0.346 AC XY: 25741 AN XY: 74330

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.306

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.476

Gnomad4 OTH AF: 0.381

Alfa AF: 0.437 Hom.: 5386

Bravo AF: 0.326

Asia WGS AF: 0.268 AC: 933 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
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: rs4647601; hg19: chr4-185570032;