4-184627976-G-T

Position:

• chr4-184627976-G-T

Variant summary

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

The NM_004346.4(CASP3):​c.*1296C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,490 control chromosomes in the GnomAD database, including 19,030 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 (19006 hom., cov: 34)
  • Exomes 𝑓: 0.41 (24 hom.)
• Consequence: CASP3 NM_004346.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.146

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 (EAS) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP3	NM_004346.4	c.*1296C>A		3_prime_UTR_variant	8/8	ENST00000308394.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP3	ENST00000308394.9	c.*1296C>A		3_prime_UTR_variant	8/8	1	NM_004346.4	P1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74545 AN: 152012 Hom.: 18958 Cov.: 34

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.490

GnomAD4 exome AF: 0.414 AC: 150 AN: 362 Hom.: 24 Cov.: 0 AF XY: 0.410 AC XY: 87 AN XY: 212

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.491 AC: 74649 AN: 152128 Hom.: 19006 Cov.: 34 AF XY: 0.497 AC XY: 36943 AN XY: 74370

Gnomad4 AFR AF: 0.467

Gnomad4 AMR AF: 0.621

Gnomad4 ASJ AF: 0.481

Gnomad4 EAS AF: 0.827

Gnomad4 SAS AF: 0.579

Gnomad4 FIN AF: 0.424

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.490

Alfa AF: 0.468 Hom.: 5902

Bravo AF: 0.507

Asia WGS AF: 0.665 AC: 2310 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	0.68
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6948; hg19: chr4-185549130;