Genetic Variant CASP3:c.*1296C>A (chr4-184627976-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004346.4(CASP3):c.*1296C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,490 control chromosomes in the GnomAD database, including 19,030 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 0.49 ( 19006 hom., cov: 34)

Exomes 𝑓: 0.41 ( 24 hom. )

Consequence

CASP3
NM_004346.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.146

Publications

32 publications found

Variant links:

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]

CASP3 links:

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ACMG classification

Classification was made for transcript

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 = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP3	NM_004346.4 link	c.*1296C>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000308394.9	NP_004337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9 link	c.*1296C>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_004346.4	ENSP00000311032.4

Frequencies

GnomAD3 genomes

AF:

0.490

AC:

74545

AN:

152012

Hom.:

18958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.466

Gnomad AMI

AF:

0.458

Gnomad AMR

AF:

0.620

Gnomad ASJ

AF:

0.481

Gnomad EAS

AF:

0.828

Gnomad SAS

AF:

0.580

Gnomad FIN

AF:

0.424

Gnomad MID

AF:

0.465

Gnomad NFE

AF:

0.455

Gnomad OTH

AF:

0.490

GnomAD4 exome

AF:

0.414

AC:

150

AN:

362

Hom.:

Cov.:

AF XY:

0.410

AC XY:

AN XY:

212

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.411

AC:

144

AN:

350

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.491

AC:

74649

AN:

152128

Hom.:

19006

Cov.:

AF XY:

0.497

AC XY:

36943

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.467

AC:

19374

AN:

41496

American (AMR)

AF:

0.621

AC:

9503

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.481

AC:

1666

AN:

3466

East Asian (EAS)

AF:

0.827

AC:

4288

AN:

5184

South Asian (SAS)

AF:

0.579

AC:

2793

AN:

4824

European-Finnish (FIN)

AF:

0.424

AC:

4479

AN:

10560

Middle Eastern (MID)

AF:

0.476

AC:

140

AN:

294

European-Non Finnish (NFE)

AF:

0.455

AC:

30955

AN:

67986

Other (OTH)

AF:

0.490

AC:

1035

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1942

3884

5825

7767

9709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

672

1344

2016

2688

3360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.472

Hom.:

7772

Bravo

AF:

0.507

Asia WGS

AF:

0.665

AC:

2310

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

0.68

(source)

DANN

Benign

0.74

PhyloP100

-0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over