rs62339863

Variant names:

• chr4-184649313-A-C
• rs62339863
• NM_004346.4:c.-183+82T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004346.4(CASP3):​c.-183+82T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 153,076 control chromosomes in the GnomAD database, including 7,079 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 0.29 (7025 hom., cov: 35)
  • Exomes 𝑓: 0.29 (54 hom.)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.96
• Publications: 10 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]

PRIMPOL (HGNC:26575): (primase and DNA directed polymerase) This gene encodes a DNA primase-polymerase that belongs to a superfamily of archaeao-eukaryotic primases. Members of this family have primase activity, catalyzing the synthesis of short RNA primers that serve as starting points for DNA synthesis, as well as DNA polymerase activity. The encoded protein facilitates DNA damage tolerance by mediating uninterrupted fork progression after UV irradiation and reinitiating DNA synthesis. An allelic variant in this gene is associated with myopia 22. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.658 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	NM_004346.4	MANE Select	c.-183+82T>G		intron	N/A	NP_004337.2
	CASP3	NM_001354777.2		c.-145+82T>G		intron	N/A	NP_001341706.1	P42574
	CASP3	NM_032991.3		c.-16+82T>G		intron	N/A	NP_116786.1	P42574

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	ENST00000308394.9	TSL:1 MANE Select	c.-183+82T>G		intron	N/A	ENSP00000311032.4	P42574
	CASP3	ENST00000523916.5	TSL:1	c.-16+82T>G		intron	N/A	ENSP00000428929.1	P42574
	CASP3	ENST00000872342.1		c.-388T>G		5_prime_UTR	Exon 1 of 8	ENSP00000542401.1

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43404 AN: 151892 Hom.: 7020 Cov.: 35

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.678

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.333

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.313

GnomAD4 exome AF: 0.286 AC: 305 AN: 1066 Hom.: 54 AF XY: 0.268 AC XY: 175 AN XY: 654

African (AFR) AF: 0.143 AC: 2 AN: 14

American (AMR) AF: 0.667 AC: 4 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 1 AN: 6

East Asian (EAS) AF: 0.583 AC: 56 AN: 96

South Asian (SAS) AF: 0.625 AC: 5 AN: 8

European-Finnish (FIN) AF: 0.333 AC: 24 AN: 72

Middle Eastern (MID) AF: 0.188 AC: 3 AN: 16

European-Non Finnish (NFE) AF: 0.246 AC: 197 AN: 802

Other (OTH) AF: 0.283 AC: 13 AN: 46

GnomAD4 genome AF: 0.286 AC: 43442 AN: 152010 Hom.: 7025 Cov.: 35 AF XY: 0.294 AC XY: 21847 AN XY: 74296

African (AFR) AF: 0.189 AC: 7828 AN: 41504

American (AMR) AF: 0.412 AC: 6297 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1047 AN: 3472

East Asian (EAS) AF: 0.677 AC: 3473 AN: 5130

South Asian (SAS) AF: 0.406 AC: 1961 AN: 4828

European-Finnish (FIN) AF: 0.287 AC: 3037 AN: 10576

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.277 AC: 18794 AN: 67900

Other (OTH) AF: 0.311 AC: 656 AN: 2112

Alfa AF: 0.270 Hom.: 710

Bravo AF: 0.294

Asia WGS AF: 0.502 AC: 1742 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.024
DANN	Benign	0.20
PhyloP100		-5.0
PromoterAI		-0.045	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62339863; hg19: chr4-185570467; COSMIC: COSV57725942; COSMIC: COSV57725942;