rs4647601

Variant names:

• chr4-184648878-C-A
• rs4647601
• NM_004346.4:c.-182-247G>T

Variant summary

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

The NM_004346.4(CASP3):​c.-182-247G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,078 control chromosomes in the GnomAD database, including 11,109 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 0.35 (11109 hom., cov: 33)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.635
• Publications: 24 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 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.-182-247G>T		intron	N/A	NP_004337.2
	CASP3	NM_001354777.2		c.-144-247G>T		intron	N/A	NP_001341706.1	P42574
	CASP3	NM_032991.3		c.-16+517G>T		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.-182-247G>T		intron	N/A	ENSP00000311032.4	P42574
	CASP3	ENST00000523916.5	TSL:1	c.-16+517G>T		intron	N/A	ENSP00000428929.1	P42574
	CASP3	ENST00000700100.1		c.-429G>T		5_prime_UTR	Exon 1 of 7	ENSP00000514797.1	P42574

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53016 AN: 151958 Hom.: 11108 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.379

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.349 AC: 53024 AN: 152078 Hom.: 11109 Cov.: 33 AF XY: 0.346 AC XY: 25741 AN XY: 74330

African (AFR) AF: 0.132 AC: 5491 AN: 41554

American (AMR) AF: 0.306 AC: 4679 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1556 AN: 3464

East Asian (EAS) AF: 0.153 AC: 792 AN: 5162

South Asian (SAS) AF: 0.368 AC: 1773 AN: 4822

European-Finnish (FIN) AF: 0.475 AC: 5016 AN: 10566

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.476 AC: 32328 AN: 67900

Other (OTH) AF: 0.381 AC: 804 AN: 2112

Alfa AF: 0.426 Hom.: 28782

Bravo AF: 0.326

Asia WGS AF: 0.268 AC: 933 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		-0.64
PromoterAI		-0.14	Neutral
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: rs4647601; hg19: chr4-185570032;