4-184629610-T-C

Position:

• chr4-184629610-T-C

Variant summary

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

The NM_004346.4(CASP3):​c.605-109A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 692,774 control chromosomes in the GnomAD database, including 39,715 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 0.32 (7780 hom., cov: 32)
  • Exomes 𝑓: 0.31 (31935 hom.)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.267

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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP3	NM_004346.4	c.605-109A>G		intron_variant		ENST00000308394.9	NP_004337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9	c.605-109A>G		intron_variant		1	NM_004346.4	ENSP00000311032	P1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 44364 AN: 140260 Hom.: 7769 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.826

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.319

GnomAD4 exome AF: 0.308 AC: 169976 AN: 552404 Hom.: 31935 AF XY: 0.311 AC XY: 89301 AN XY: 287326

Gnomad4 AFR exome AF: 0.208

Gnomad4 AMR exome AF: 0.505

Gnomad4 ASJ exome AF: 0.245

Gnomad4 EAS exome AF: 0.806

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.316 AC: 44398 AN: 140370 Hom.: 7780 Cov.: 32 AF XY: 0.329 AC XY: 22328 AN XY: 67968

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.826

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.317

Alfa AF: 0.274 Hom.: 3284

Bravo AF: 0.307

Asia WGS AF: 0.573 AC: 1987 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.8
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4647693; hg19: chr4-185550764;