4-184648647-G-T

Position:

• chr4-184648647-G-T

Variant summary

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

The ENST00000308394.9(CASP3):​c.-182-16C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 155,138 control chromosomes in the GnomAD database, including 1,834 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 0.10 (1791 hom., cov: 32)
  • Exomes 𝑓: 0.12 (43 hom.)
• Consequence: CASP3 ENST00000308394.9 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78

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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP3	NM_004346.4	c.-182-16C>A		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.-182-16C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004346.4	ENSP00000311032	P1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15538 AN: 152082 Hom.: 1790 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.0861

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0748

Gnomad OTH AF: 0.0962

GnomAD4 exome AF: 0.124 AC: 364 AN: 2938 Hom.: 43 Cov.: 0 AF XY: 0.121 AC XY: 187 AN XY: 1544

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.0854

Gnomad4 EAS exome AF: 0.448

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.0732

Gnomad4 NFE exome AF: 0.0778

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.102 AC: 15547 AN: 152200 Hom.: 1791 Cov.: 32 AF XY: 0.110 AC XY: 8186 AN XY: 74422

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.0718

Gnomad4 EAS AF: 0.585

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.0861

Gnomad4 NFE AF: 0.0748

Gnomad4 OTH AF: 0.0966

Alfa AF: 0.0360 Hom.: 41

Bravo AF: 0.116

Asia WGS AF: 0.335 AC: 1161 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.8
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4647602; hg19: chr4-185569801;