rs2705897

Positions:

• chr4-184631944-T-G

Variant summary

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

The NM_004346.4(CASP3):​c.308-4A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,591,920 control chromosomes in the GnomAD database, including 409,358 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (40660 hom., cov: 31)
  • Exomes 𝑓: 0.71 (368698 hom.)
• Consequence: CASP3 NM_004346.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001778
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP3	NM_004346.4	c.308-4A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000308394.9	NP_004337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9	c.308-4A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004346.4	ENSP00000311032	P1

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109144 AN: 151842 Hom.: 40604 Cov.: 31

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.701

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.755

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.738

Gnomad OTH AF: 0.725

GnomAD3 exomes AF: 0.645 AC: 149753 AN: 232198 Hom.: 52117 AF XY: 0.653 AC XY: 82211 AN XY: 125862

Gnomad AFR exome AF: 0.820

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.750

Gnomad EAS exome AF: 0.176

Gnomad SAS exome AF: 0.598

Gnomad FIN exome AF: 0.744

Gnomad NFE exome AF: 0.736

Gnomad OTH exome AF: 0.683

GnomAD4 exome AF: 0.707 AC: 1017838 AN: 1439960 Hom.: 368698 Cov.: 32 AF XY: 0.705 AC XY: 504967 AN XY: 716228

Gnomad4 AFR exome AF: 0.838

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.752

Gnomad4 EAS exome AF: 0.195

Gnomad4 SAS exome AF: 0.602

Gnomad4 FIN exome AF: 0.742

Gnomad4 NFE exome AF: 0.736

Gnomad4 OTH exome AF: 0.693

GnomAD4 genome AF: 0.719 AC: 109252 AN: 151960 Hom.: 40660 Cov.: 31 AF XY: 0.710 AC XY: 52746 AN XY: 74254

Gnomad4 AFR AF: 0.820

Gnomad4 AMR AF: 0.552

Gnomad4 ASJ AF: 0.755

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.747

Gnomad4 NFE AF: 0.738

Gnomad4 OTH AF: 0.727

Alfa AF: 0.732 Hom.: 53898

Bravo AF: 0.705

Asia WGS AF: 0.434 AC: 1513 AN: 3478

EpiCase AF: 0.741

EpiControl AF: 0.742

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.074
SpliceAI score (max)		0.020		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: rs2705897; hg19: chr4-185553098;