4-184645627-C-T

Variant names:

• chr4-184645627-C-T
• rs4647617
• NM_004346.4:c.-16+2838G>A

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+2838G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,120 control chromosomes in the GnomAD database, including 3,204 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 0.17 (3204 hom., cov: 32)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.334
• Publications: 1 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP3	NM_004346.4	c.-16+2838G>A		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+2838G>A		intron_variant	Intron 2 of 7	1	NM_004346.4	ENSP00000311032.4

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25738 AN: 152002 Hom.: 3200 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.160

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

GnomAD4 genome AF: 0.169 AC: 25755 AN: 152120 Hom.: 3204 Cov.: 32 AF XY: 0.177 AC XY: 13176 AN XY: 74356

African (AFR) AF: 0.110 AC: 4565 AN: 41508

American (AMR) AF: 0.297 AC: 4537 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 510 AN: 3470

East Asian (EAS) AF: 0.677 AC: 3492 AN: 5160

South Asian (SAS) AF: 0.302 AC: 1455 AN: 4812

European-Finnish (FIN) AF: 0.140 AC: 1484 AN: 10566

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9205 AN: 67996

Other (OTH) AF: 0.161 AC: 340 AN: 2116

Alfa AF: 0.142 Hom.: 216

Bravo AF: 0.181

Asia WGS AF: 0.445 AC: 1542 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.2
DANN	Benign	0.82
PhyloP100		-0.33
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: rs4647617; hg19: chr4-185566781;