rs59760601

Positions:

• chr4-184644689-G-A

Variant summary

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

The NM_001354783.2(CASP3):​c.-147C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 354,102 control chromosomes in the GnomAD database, including 8,999 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 0.17 (3205 hom., cov: 32)
  • Exomes 𝑓: 0.20 (5794 hom.)
• Consequence: CASP3 NM_001354783.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.253

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]

CASP3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP3	NM_004346.4	c.-16+3776C>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.-16+3776C>T		intron_variant		1	NM_004346.4	ENSP00000311032.4

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25746 AN: 151958 Hom.: 3201 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.678

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.203 AC: 41107 AN: 202026 Hom.: 5794 Cov.: 0 AF XY: 0.210 AC XY: 24344 AN XY: 116186

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.365

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.696

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.169 AC: 25763 AN: 152076 Hom.: 3205 Cov.: 32 AF XY: 0.177 AC XY: 13181 AN XY: 74336

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.297

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.678

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.160

Alfa AF: 0.143 Hom.: 211

Bravo AF: 0.181

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.7
DANN	Benign	0.84

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: rs59760601; hg19: chr4-185565843; COSMIC: COSV57726140; COSMIC: COSV57726140;