4-184638333-G-A

Variant names:

• chr4-184638333-G-A
• rs2705901
• NM_004346.4:c.53+68C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004346.4(CASP3):​c.53+68C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319
• Publications: 7 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004346.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	NM_004346.4	MANE Select	c.53+68C>T		intron	N/A	NP_004337.2
	CASP3	NM_001354777.2		c.53+68C>T		intron	N/A	NP_001341706.1
	CASP3	NM_032991.3		c.53+68C>T		intron	N/A	NP_116786.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	ENST00000308394.9	TSL:1 MANE Select	c.53+68C>T		intron	N/A	ENSP00000311032.4
	CASP3	ENST00000523916.5	TSL:1	c.53+68C>T		intron	N/A	ENSP00000428929.1
	CASP3	ENST00000393585.6	TSL:1	c.53+68C>T		intron	N/A	ENSP00000377210.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 676014 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 359052

African (AFR) AF: 0.00 AC: 0 AN: 17314

American (AMR) AF: 0.00 AC: 0 AN: 34546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18984

East Asian (EAS) AF: 0.00 AC: 0 AN: 34466

South Asian (SAS) AF: 0.00 AC: 0 AN: 61256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4174

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 421730

Other (OTH) AF: 0.00 AC: 0 AN: 33662

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.94
PhyloP100		-0.32

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: rs2705901; hg19: chr4-185559487;