rs59760601

Variant names:

• chr4-184644689-G-A
• rs59760601
• ENST00000393585.6:c.-174C>T

Variant summary

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

The NM_001354783.2(CASP3):​c.-147C>T 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 0.189 in 354,102 control chromosomes in the GnomAD database, including 8,999 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 (3205 hom., cov: 32)
  • Exomes 𝑓: 0.20 (5794 hom.)
• Consequence: CASP3 NM_001354783.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.253
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354783.2. 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.-16+3776C>T		intron	N/A	NP_004337.2
	CASP3	NM_001354783.2		c.-147C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	NP_001341712.1
	CASP3	NM_001354783.2		c.-147C>T		5_prime_UTR	Exon 3 of 8	NP_001341712.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	ENST00000393585.6	TSL:1	c.-174C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000377210.2	A8MVM1
	CASP3	ENST00000393585.6	TSL:1	c.-174C>T		5_prime_UTR	Exon 2 of 7	ENSP00000377210.2	A8MVM1
	CASP3	ENST00000308394.9	TSL:1 MANE Select	c.-16+3776C>T		intron	N/A	ENSP00000311032.4	P42574

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25746 AN: 151958 Hom.: 3201 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.678

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.203 AC: 41107 AN: 202026 Hom.: 5794 Cov.: 0 AF XY: 0.210 AC XY: 24344 AN XY: 116186

African (AFR) AF: 0.119 AC: 539 AN: 4544

American (AMR) AF: 0.365 AC: 4843 AN: 13276

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 914 AN: 6466

East Asian (EAS) AF: 0.696 AC: 4670 AN: 6710

South Asian (SAS) AF: 0.289 AC: 11235 AN: 38820

European-Finnish (FIN) AF: 0.141 AC: 3141 AN: 22270

Middle Eastern (MID) AF: 0.131 AC: 92 AN: 700

European-Non Finnish (NFE) AF: 0.140 AC: 14045 AN: 100498

Other (OTH) AF: 0.186 AC: 1628 AN: 8742

GnomAD4 genome AF: 0.169 AC: 25763 AN: 152076 Hom.: 3205 Cov.: 32 AF XY: 0.177 AC XY: 13181 AN XY: 74336

African (AFR) AF: 0.110 AC: 4573 AN: 41486

American (AMR) AF: 0.297 AC: 4529 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 510 AN: 3472

East Asian (EAS) AF: 0.678 AC: 3502 AN: 5168

South Asian (SAS) AF: 0.301 AC: 1451 AN: 4818

European-Finnish (FIN) AF: 0.140 AC: 1481 AN: 10556

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

European-Non Finnish (NFE) AF: 0.135 AC: 9213 AN: 67998

Other (OTH) AF: 0.160 AC: 337 AN: 2112

Alfa AF: 0.143 Hom.: 211

Bravo AF: 0.181

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.7
DANN	Benign	0.84
PhyloP100		-0.25
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs59760601;

hg19: chr4-185565843;

COSMIC: COSV57726140;

COSMIC: COSV57726140;