ENST00000393585.6:c.549A>G

Variant names:

• chr4-184629436-T-C
• ENST00000393585.6:c.549A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The ENST00000393585.6(CASP3):​c.549A>G​(p.Ter183Trpext*?) variant causes a stop lost 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CASP3 ENST00000393585.6 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in ENST00000393585.6 Downstream stopcodon found after 10 codons.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000393585.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	NM_004346.4	MANE Select	c.670A>G	p.Lys224Glu	missense	Exon 8 of 8	NP_004337.2
	CASP3	NM_001354783.2		c.576A>G	p.Ter192Trpext*?	stop_lost	Exon 8 of 8	NP_001341712.1
	CASP3	NM_001354781.2		c.549A>G	p.Ter183Trpext*?	stop_lost	Exon 6 of 6	NP_001341710.1	A8MVM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	ENST00000393585.6	TSL:1	c.549A>G	p.Ter183Trpext*?	stop_lost	Exon 7 of 7	ENSP00000377210.2	A8MVM1
	CASP3	ENST00000308394.9	TSL:1 MANE Select	c.670A>G	p.Lys224Glu	missense	Exon 8 of 8	ENSP00000311032.4	P42574
	CASP3	ENST00000523916.5	TSL:1	c.670A>G	p.Lys224Glu	missense	Exon 7 of 7	ENSP00000428929.1	P42574

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.79
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.0032
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.059
Sift	Benign	0.77	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.061
MutPred		0.48		Loss of ubiquitination at K224 (P = 0.0326)
MVP		0.76
MPC		1.2
ClinPred		0.35	T
GERP RS		4.5
Varity_R		0.34
gMVP		0.64
Mutation Taster		=14/186	disease causing

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

hg19: chr4-185550590;