4-184638333-G-C

Variant summary

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

The NM_004346.4(CASP3):c.53+68C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 827,064 control chromosomes in the GnomAD database, including 304,820 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 0.88 (59412 hom., cov: 31)
  • Exomes 𝑓: 0.85 (245408 hom.)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319

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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP3	NM_004346.4	c.53+68C>G		intron_variant		ENST00000308394.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP3	ENST00000308394.9	c.53+68C>G		intron_variant		1	NM_004346.4	P1

Frequencies

GnomAD3 genomes AF: 0.882 AC: 134088 AN: 152092 Hom.: 59341 Cov.: 31

Gnomad AFR AF: 0.952

Gnomad AMI AF: 0.837

Gnomad AMR AF: 0.821

Gnomad ASJ AF: 0.848

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.923

Gnomad MID AF: 0.876

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.868

GnomAD4 exome AF: 0.852 AC: 574957 AN: 674854 Hom.: 245408 AF XY: 0.852 AC XY: 305300 AN XY: 358414

Gnomad4 AFR exome AF: 0.957

Gnomad4 AMR exome AF: 0.785

Gnomad4 ASJ exome AF: 0.836

Gnomad4 EAS exome AF: 0.858

Gnomad4 SAS exome AF: 0.845

Gnomad4 FIN exome AF: 0.911

Gnomad4 NFE exome AF: 0.847

Gnomad4 OTH exome AF: 0.857

GnomAD4 genome AF: 0.882 AC: 134222 AN: 152210 Hom.: 59412 Cov.: 31 AF XY: 0.883 AC XY: 65725 AN XY: 74424

Gnomad4 AFR AF: 0.952

Gnomad4 AMR AF: 0.821

Gnomad4 ASJ AF: 0.848

Gnomad4 EAS AF: 0.879

Gnomad4 SAS AF: 0.838

Gnomad4 FIN AF: 0.923

Gnomad4 NFE AF: 0.852

Gnomad4 OTH AF: 0.871

Alfa AF: 0.872 Hom.: 7195

Bravo AF: 0.877

Asia WGS AF: 0.858 AC: 2984 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
Cadd	Benign	2.9
Dann	Benign	0.51

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: rs2705901; hg19: chr4-185559487;