rs2019978

Positions:

• chr4-184636427-A-C

Variant summary

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

The ENST00000308394.9(CASP3):​c.54-1009T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 151,986 control chromosomes in the GnomAD database, including 2,582 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 0.18 (2582 hom., cov: 31)
• Consequence: CASP3 ENST00000308394.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373

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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP3	NM_004346.4	c.54-1009T>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.54-1009T>G		intron_variant		1	NM_004346.4	ENSP00000311032	P1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27189 AN: 151868 Hom.: 2573 Cov.: 31

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.194

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.179 AC: 27246 AN: 151986 Hom.: 2582 Cov.: 31 AF XY: 0.176 AC XY: 13087 AN XY: 74296

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.196

Alfa AF: 0.195 Hom.: 6148

Bravo AF: 0.179

Asia WGS AF: 0.0690 AC: 243 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.49

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: rs2019978; hg19: chr4-185557581;