4-184638432-C-T

Variant names:

• chr4-184638432-C-T
• rs950745993
• NM_004346.4:c.22G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001354779.2(CASP3):​c.-53G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000255 in 1,569,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CASP3 NM_001354779.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2860941).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354779.2. 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.22G>A	p.Val8Met	missense	Exon 3 of 8	NP_004337.2
	CASP3	NM_001354779.2		c.-53G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001341708.1
	CASP3	NM_001354780.2		c.-53G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	NP_001341709.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	ENST00000308394.9	TSL:1 MANE Select	c.22G>A	p.Val8Met	missense	Exon 3 of 8	ENSP00000311032.4	P42574
	CASP3	ENST00000523916.5	TSL:1	c.22G>A	p.Val8Met	missense	Exon 2 of 7	ENSP00000428929.1	P42574
	CASP3	ENST00000393585.6	TSL:1	c.22G>A	p.Val8Met	missense	Exon 3 of 7	ENSP00000377210.2	A8MVM1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1417802 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 708024

African (AFR) AF: 0.00 AC: 0 AN: 32622

American (AMR) AF: 0.00 AC: 0 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25790

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.00 AC: 0 AN: 84698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1073436

Other (OTH) AF: 0.00 AC: 0 AN: 58856

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.069
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.43
MutPred		0.20		Gain of glycosylation at S7 (P = 0.0233)
MVP		0.94
MPC		1.2
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.087
gMVP		0.72
Mutation Taster		=97/3	polymorphism

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: rs950745993; hg19: chr4-185559586;