Genetic Variant CASP3:c.-183+116C>T (chr4-184649279-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_004346.4(CASP3):c.-183+116C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 152,586 control chromosomes in the GnomAD database, including 465 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 0.045 ( 465 hom., cov: 34)

Exomes 𝑓: 0.0088 ( 0 hom. )

Consequence

CASP3
NM_004346.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.908

Publications

3 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 -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004346.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CASP3	NM_004346.4	MANE Select	c.-183+116C>T	intron	N/A	NP_004337.2
CASP3	NM_001354777.2		c.-145+116C>T	intron	N/A	NP_001341706.1
CASP3	NM_032991.3		c.-16+116C>T	intron	N/A	NP_116786.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CASP3	ENST00000308394.9	TSL:1 MANE Select	c.-183+116C>T	intron	N/A	ENSP00000311032.4
CASP3	ENST00000523916.5	TSL:1	c.-16+116C>T	intron	N/A	ENSP00000428929.1
CASP3	ENST00000700101.1		c.-16+713C>T	intron	N/A	ENSP00000514798.1

Frequencies

GnomAD3 genomes

AF:

0.0453

AC:

6883

AN:

152014

Hom.:

465

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.0414

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.0345

GnomAD4 exome

AF:

0.00877

AC:

AN:

456

Hom.:

AF XY:

0.00

AC XY:

AN XY:

276

show subpopulations

African (AFR)

AF:

0.200

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00294

AC:

AN:

340

Other (OTH)

AF:

0.0385

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.0453

AC:

6888

AN:

152130

Hom.:

465

Cov.:

AF XY:

0.0435

AC XY:

3237

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.150

AC:

6212

AN:

41506

American (AMR)

AF:

0.0212

AC:

324

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

113

AN:

3472

East Asian (EAS)

AF:

0.000388

AC:

AN:

5150

South Asian (SAS)

AF:

0.00104

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0377

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00210

AC:

143

AN:

67970

Other (OTH)

AF:

0.0341

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

302

605

907

1210

1512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0229

Hom.:

Bravo

AF:

0.0521

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

9.4

(source)

DANN

Benign

0.95

PhyloP100

-0.91

PromoterAI

-0.052

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: 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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over