4-184646959-C-G

Variant names:

• chr4-184646959-C-G
• rs2720378
• NM_004346.4:c.-16+1506G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004346.4(CASP3):​c.-16+1506G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 151,250 control chromosomes in the GnomAD database, including 12,470 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 0.39 (12470 hom., cov: 31)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950
• Publications: 18 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP3	NM_004346.4	c.-16+1506G>C		intron_variant	Intron 2 of 7	ENST00000308394.9	NP_004337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9	c.-16+1506G>C		intron_variant	Intron 2 of 7	1	NM_004346.4	ENSP00000311032.4

Frequencies

GnomAD3 genomes AF: 0.389 AC: 58864 AN: 151134 Hom.: 12455 Cov.: 31

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.389

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

GnomAD4 genome AF: 0.390 AC: 58943 AN: 151250 Hom.: 12470 Cov.: 31 AF XY: 0.396 AC XY: 29256 AN XY: 73890

African (AFR) AF: 0.509 AC: 20802 AN: 40836

American (AMR) AF: 0.470 AC: 7159 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1238 AN: 3472

East Asian (EAS) AF: 0.684 AC: 3534 AN: 5168

South Asian (SAS) AF: 0.435 AC: 2085 AN: 4794

European-Finnish (FIN) AF: 0.299 AC: 3138 AN: 10510

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.291 AC: 19793 AN: 67946

Other (OTH) AF: 0.390 AC: 821 AN: 2104

Alfa AF: 0.171 Hom.: 309

Bravo AF: 0.409

Asia WGS AF: 0.537 AC: 1866 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.6
DANN	Benign	0.56
PhyloP100		-0.095
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2720378; hg19: chr4-185568113;