rs1049216

Positions:

• chr4-184628935-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000308394.9(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 ENST00000308394.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.749

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
CASP3	NM_004346.4	c.*337T>C		3_prime_UTR_variant	8/8	ENST00000308394.9	NP_004337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9	c.*337T>C		3_prime_UTR_variant	8/8	1	NM_004346.4	ENSP00000311032	P1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42225 AN: 152058 Hom.: 7297 Cov.: 32

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.: 0 AF XY: 0.307 AC XY: 6078 AN XY: 19814

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.476

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.816

Gnomad4 SAS exome AF: 0.390

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.278 AC: 42238 AN: 152176 Hom.: 7304 Cov.: 32 AF XY: 0.286 AC XY: 21298 AN XY: 74394

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.446

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.821

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.269

Alfa AF: 0.253 Hom.: 781

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	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
DANN	Benign	0.74

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

LitVar

Other links and lift over

dbSNP: rs1049216; hg19: chr4-185550089;