Genetic Variant CASP3:c.53+68C>G (chr4-184638333-G-C) – 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.53+68C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 827,064 control chromosomes in the GnomAD database, including 304,820 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 0.88 ( 59412 hom., cov: 31)

Exomes 𝑓: 0.85 ( 245408 hom. )

Consequence

CASP3
NM_004346.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.319

Publications

7 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=-0.99).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP3	NM_004346.4 link	c.53+68C>G		intron_variant	Intron 3 of 7	ENST00000308394.9	NP_004337.2	P42574

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9 link	c.53+68C>G		intron_variant	Intron 3 of 7	1	NM_004346.4	ENSP00000311032.4		P42574

Frequencies

GnomAD3 genomes

AF:

0.882

AC:

134088

AN:

152092

Hom.:

59341

Cov.:

show subpopulations

Gnomad AFR

AF:

0.952

Gnomad AMI

AF:

0.837

Gnomad AMR

AF:

0.821

Gnomad ASJ

AF:

0.848

Gnomad EAS

AF:

0.879

Gnomad SAS

AF:

0.836

Gnomad FIN

AF:

0.923

Gnomad MID

AF:

0.876

Gnomad NFE

AF:

0.852

Gnomad OTH

AF:

0.868

GnomAD4 exome

AF:

0.852

AC:

574957

AN:

674854

Hom.:

245408

AF XY:

0.852

AC XY:

305300

AN XY:

358414

show subpopulations

African (AFR)

AF:

0.957

AC:

16548

AN:

17300

American (AMR)

AF:

0.785

AC:

27035

AN:

34454

Ashkenazi Jewish (ASJ)

AF:

0.836

AC:

15837

AN:

18938

East Asian (EAS)

AF:

0.858

AC:

29545

AN:

34426

South Asian (SAS)

AF:

0.845

AC:

51647

AN:

61148

European-Finnish (FIN)

AF:

0.911

AC:

45435

AN:

49852

Middle Eastern (MID)

AF:

0.891

AC:

3713

AN:

4168

European-Non Finnish (NFE)

AF:

0.847

AC:

356368

AN:

420948

Other (OTH)

AF:

0.857

AC:

28829

AN:

33620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

3950

7899

11849

15798

19748

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.882

AC:

134222

AN:

152210

Hom.:

59412

Cov.:

AF XY:

0.883

AC XY:

65725

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.952

AC:

39554

AN:

41536

American (AMR)

AF:

0.821

AC:

12542

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.848

AC:

2942

AN:

3470

East Asian (EAS)

AF:

0.879

AC:

4548

AN:

5174

South Asian (SAS)

AF:

0.838

AC:

4040

AN:

4822

European-Finnish (FIN)

AF:

0.923

AC:

9783

AN:

10596

Middle Eastern (MID)

AF:

0.880

AC:

257

AN:

292

European-Non Finnish (NFE)

AF:

0.852

AC:

57959

AN:

68024

Other (OTH)

AF:

0.871

AC:

1837

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

796

1592

2387

3183

3979

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.872

Hom.:

7195

Bravo

AF:

0.877

Asia WGS

AF:

0.858

AC:

2984

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

2.9

(source)

DANN

Benign

0.51

PhyloP100

-0.32

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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4-184638333-G-C

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