Genetic Variant NM_004346.4:c.*337T>C (chr4-184628935-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004346.4(CASP3):c.*337T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 190,686 control chromosomes in the GnomAD database, including 9,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 7304 hom., cov: 32)

Exomes 𝑓: 0.30 ( 2219 hom. )

Consequence

CASP3
NM_004346.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.749

Publications

41 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 4-184628935-A-G is Benign according to our data. Variant chr4-184628935-A-G is described in ClinVar as [Benign]. Clinvar id is 1255108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP3	NM_004346.4 link	c.*337T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000308394.9	NP_004337.2	P42574

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9 link	c.*337T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_004346.4	ENSP00000311032.4		P42574

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42225

AN:

152058

Hom.:

7297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.445

Gnomad ASJ

AF:

0.245

Gnomad EAS

AF:

0.822

Gnomad SAS

AF:

0.415

Gnomad FIN

AF:

0.253

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.262

Gnomad OTH

AF:

0.270

GnomAD4 exome

AF:

0.300

AC:

11562

AN:

38510

Hom.:

2219

Cov.:

AF XY:

0.307

AC XY:

6078

AN XY:

19814

show subpopulations

African (AFR)

AF:

0.154

AC:

122

AN:

794

American (AMR)

AF:

0.476

AC:

987

AN:

2074

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

255

AN:

1162

East Asian (EAS)

AF:

0.816

AC:

1317

AN:

1614

South Asian (SAS)

AF:

0.390

AC:

1694

AN:

4340

European-Finnish (FIN)

AF:

0.251

AC:

515

AN:

2048

Middle Eastern (MID)

AF:

0.220

AC:

AN:

150

European-Non Finnish (NFE)

AF:

0.249

AC:

5989

AN:

24054

Other (OTH)

AF:

0.286

AC:

650

AN:

2274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

359

719

1078

1438

1797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.278

AC:

42238

AN:

152176

Hom.:

7304

Cov.:

AF XY:

0.286

AC XY:

21298

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.167

AC:

6931

AN:

41518

American (AMR)

AF:

0.446

AC:

6817

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.245

AC:

850

AN:

3470

East Asian (EAS)

AF:

0.821

AC:

4252

AN:

5178

South Asian (SAS)

AF:

0.413

AC:

1993

AN:

4822

European-Finnish (FIN)

AF:

0.253

AC:

2675

AN:

10584

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.262

AC:

17817

AN:

67992

Other (OTH)

AF:

0.269

AC:

568

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1422

2844

4266

5688

7110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.249

Hom.:

2277

Bravo

AF:

0.291

Asia WGS

AF:

0.568

AC:

1971

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 23, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28114230) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.7

(source)

DANN

Benign

0.74

PhyloP100

0.75

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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NM_004346.4:c.*337T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over