4-184628935-A-G

Variant names:

• chr4-184628935-A-G
• rs1049216
• NM_004346.4:c.*337T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.749
• Publications: 41 publications found

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

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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	NM_004346.4	MANE Select	c.*337T>C		3_prime_UTR	Exon 8 of 8	NP_004337.2
	CASP3	NM_001354777.2		c.*337T>C		3_prime_UTR	Exon 8 of 8	NP_001341706.1
	CASP3	NM_032991.3		c.*337T>C		3_prime_UTR	Exon 7 of 7	NP_116786.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	ENST00000308394.9	TSL:1 MANE Select	c.*337T>C		3_prime_UTR	Exon 8 of 8	ENSP00000311032.4
	CASP3	ENST00000523916.5	TSL:1	c.*337T>C		3_prime_UTR	Exon 7 of 7	ENSP00000428929.1
	CASP3	ENST00000393585.6	TSL:1	c.*501T>C		3_prime_UTR	Exon 7 of 7	ENSP00000377210.2

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

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: 33 AN: 150

European-Non Finnish (NFE) AF: 0.249 AC: 5989 AN: 24054

Other (OTH) AF: 0.286 AC: 650 AN: 2274

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

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: 61 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17817 AN: 67992

Other (OTH) AF: 0.269 AC: 568 AN: 2112

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.7
DANN	Benign	0.74
PhyloP100		0.75
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1049216; hg19: chr4-185550089;