4-184643592-T-C

Variant summary

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

The NM_004346.4(CASP3):c.-16+4873A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 143,234 control chromosomes in the GnomAD database, including 20,581 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 0.49 (20581 hom., cov: 24)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.29

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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP3	NM_004346.4	c.-16+4873A>G		intron_variant		ENST00000308394.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP3	ENST00000308394.9	c.-16+4873A>G		intron_variant		1	NM_004346.4	P1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 70438 AN: 143134 Hom.: 20531 Cov.: 24

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.489

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.470

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

GnomAD4 genome AF: 0.493 AC: 70552 AN: 143234 Hom.: 20581 Cov.: 24 AF XY: 0.505 AC XY: 34555 AN XY: 68452

Gnomad4 AFR AF: 0.815

Gnomad4 AMR AF: 0.550

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.695

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.471

Alfa AF: 0.175 Hom.: 311

Bravo AF: 0.509

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	1.0
Dann	Benign	0.11

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: rs2720377; hg19: chr4-185564746;