Genetic Variant CASP3:c.605-109A>G (chr4-184629610-T-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.605-109A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 692,774 control chromosomes in the GnomAD database, including 39,715 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 0.32 ( 7780 hom., cov: 32)

Exomes 𝑓: 0.31 ( 31935 hom. )

Consequence

CASP3
NM_004346.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.267

Publications

11 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=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP3	NM_004346.4 link	c.605-109A>G		intron_variant	Intron 7 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.605-109A>G		intron_variant	Intron 7 of 7	1	NM_004346.4	ENSP00000311032.4		P42574

Frequencies

GnomAD3 genomes

AF:

0.316

AC:

44364

AN:

140260

Hom.:

7769

Cov.:

show subpopulations

Gnomad AFR

AF:

0.246

Gnomad AMI

AF:

0.319

Gnomad AMR

AF:

0.490

Gnomad ASJ

AF:

0.256

Gnomad EAS

AF:

0.826

Gnomad SAS

AF:

0.458

Gnomad FIN

AF:

0.293

Gnomad MID

AF:

0.220

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.319

GnomAD4 exome

AF:

0.308

AC:

169976

AN:

552404

Hom.:

31935

AF XY:

0.311

AC XY:

89301

AN XY:

287326

show subpopulations

African (AFR)

AF:

0.208

AC:

2878

AN:

13868

American (AMR)

AF:

0.505

AC:

7894

AN:

15632

Ashkenazi Jewish (ASJ)

AF:

0.245

AC:

3519

AN:

14342

East Asian (EAS)

AF:

0.806

AC:

24526

AN:

30424

South Asian (SAS)

AF:

0.393

AC:

17371

AN:

44174

European-Finnish (FIN)

AF:

0.256

AC:

8494

AN:

33222

Middle Eastern (MID)

AF:

0.202

AC:

631

AN:

3128

European-Non Finnish (NFE)

AF:

0.260

AC:

95678

AN:

368622

Other (OTH)

AF:

0.310

AC:

8985

AN:

28992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

5116

10231

15347

20462

25578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1640

3280

4920

6560

8200

<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:

0.316

AC:

44398

AN:

140370

Hom.:

7780

Cov.:

AF XY:

0.329

AC XY:

22328

AN XY:

67968

show subpopulations

African (AFR)

AF:

0.246

AC:

8988

AN:

36528

American (AMR)

AF:

0.491

AC:

6904

AN:

14054

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

848

AN:

3310

East Asian (EAS)

AF:

0.826

AC:

4245

AN:

5142

South Asian (SAS)

AF:

0.456

AC:

1997

AN:

4376

European-Finnish (FIN)

AF:

0.293

AC:

2648

AN:

9034

Middle Eastern (MID)

AF:

0.213

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.275

AC:

17842

AN:

64916

Other (OTH)

AF:

0.317

AC:

591

AN:

1864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1469

2938

4408

5877

7346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

448

896

1344

1792

2240

<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:

0.273

Hom.:

3615

Bravo

AF:

0.307

Asia WGS

AF:

0.573

AC:

1987

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.8

(source)

DANN

Benign

0.59

PhyloP100

0.27

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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