4-184648647-G-T

Variant names:

• chr4-184648647-G-T
• rs4647602
• NM_004346.4:c.-182-16C>A

Variant summary

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

The NM_004346.4(CASP3):​c.-182-16C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 155,138 control chromosomes in the GnomAD database, including 1,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.10 (1791 hom., cov: 32)
  • Exomes 𝑓: 0.12 (43 hom.)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• Publications: 16 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 (EAS) allele frequency at 95% confidence interval = 0.568 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.-182-16C>A		intron	N/A	NP_004337.2
	CASP3	NM_001354777.2		c.-144-16C>A		intron	N/A	NP_001341706.1	P42574
	CASP3	NM_032991.3		c.-16+748C>A		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.-182-16C>A		intron	N/A	ENSP00000311032.4	P42574
	CASP3	ENST00000523916.5	TSL:1	c.-16+748C>A		intron	N/A	ENSP00000428929.1	P42574
	CASP3	ENST00000700100.1		c.-198C>A		5_prime_UTR	Exon 1 of 7	ENSP00000514797.1	P42574

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15538 AN: 152082 Hom.: 1790 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.0861

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0748

Gnomad OTH AF: 0.0962

GnomAD4 exome AF: 0.124 AC: 364 AN: 2938 Hom.: 43 Cov.: 0 AF XY: 0.121 AC XY: 187 AN XY: 1544

African (AFR) AF: 0.0143 AC: 1 AN: 70

American (AMR) AF: 0.237 AC: 9 AN: 38

Ashkenazi Jewish (ASJ) AF: 0.0854 AC: 7 AN: 82

East Asian (EAS) AF: 0.448 AC: 146 AN: 326

South Asian (SAS) AF: 0.118 AC: 4 AN: 34

European-Finnish (FIN) AF: 0.0732 AC: 29 AN: 396

Middle Eastern (MID) AF: 0.143 AC: 2 AN: 14

European-Non Finnish (NFE) AF: 0.0778 AC: 143 AN: 1838

Other (OTH) AF: 0.164 AC: 23 AN: 140

GnomAD4 genome AF: 0.102 AC: 15547 AN: 152200 Hom.: 1791 Cov.: 32 AF XY: 0.110 AC XY: 8186 AN XY: 74422

African (AFR) AF: 0.0332 AC: 1380 AN: 41548

American (AMR) AF: 0.245 AC: 3746 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 249 AN: 3468

East Asian (EAS) AF: 0.585 AC: 3017 AN: 5158

South Asian (SAS) AF: 0.181 AC: 870 AN: 4816

European-Finnish (FIN) AF: 0.0861 AC: 914 AN: 10610

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0748 AC: 5088 AN: 68002

Other (OTH) AF: 0.0966 AC: 204 AN: 2112

Alfa AF: 0.0836 Hom.: 754

Bravo AF: 0.116

Asia WGS AF: 0.335 AC: 1161 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	9.8
DANN	Benign	0.84
PhyloP100		1.8
PromoterAI		-0.046	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: rs4647602; hg19: chr4-185569801;