4-184648576-C-T

Variant names:

• chr4-184648576-C-T
• rs4647603
• NM_004346.4:c.-127G>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.-127G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 162,014 control chromosomes in the GnomAD database, including 1,257 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 0.11 (1161 hom., cov: 31)
  • Exomes 𝑓: 0.13 (96 hom.)
• Consequence: CASP3 NM_004346.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• Publications: 31 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.149 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.-127G>A		5_prime_UTR	Exon 2 of 8	NP_004337.2
	CASP3	NM_001354777.2		c.-89G>A		5_prime_UTR	Exon 2 of 8	NP_001341706.1	P42574
	CASP3	NM_001354780.2		c.-201G>A		5_prime_UTR	Exon 2 of 8	NP_001341709.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	ENST00000308394.9	TSL:1 MANE Select	c.-127G>A		5_prime_UTR	Exon 2 of 8	ENSP00000311032.4	P42574
	CASP3	ENST00000393585.6	TSL:1	c.-319G>A		5_prime_UTR	Exon 1 of 7	ENSP00000377210.2	A8MVM1
	CASP3	ENST00000523916.5	TSL:1	c.-16+819G>A		intron	N/A	ENSP00000428929.1	P42574

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16411 AN: 152096 Hom.: 1160 Cov.: 31

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0871

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.129 AC: 1264 AN: 9800 Hom.: 96 Cov.: 0 AF XY: 0.137 AC XY: 718 AN XY: 5240

African (AFR) AF: 0.0367 AC: 8 AN: 218

American (AMR) AF: 0.189 AC: 25 AN: 132

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 50 AN: 306

East Asian (EAS) AF: 0.00 AC: 0 AN: 1104

South Asian (SAS) AF: 0.0588 AC: 4 AN: 68

European-Finnish (FIN) AF: 0.161 AC: 193 AN: 1198

Middle Eastern (MID) AF: 0.100 AC: 6 AN: 60

European-Non Finnish (NFE) AF: 0.147 AC: 905 AN: 6166

Other (OTH) AF: 0.133 AC: 73 AN: 548

GnomAD4 genome AF: 0.108 AC: 16411 AN: 152214 Hom.: 1161 Cov.: 31 AF XY: 0.109 AC XY: 8074 AN XY: 74410

African (AFR) AF: 0.0262 AC: 1089 AN: 41558

American (AMR) AF: 0.121 AC: 1845 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.0882 AC: 425 AN: 4816

European-Finnish (FIN) AF: 0.156 AC: 1652 AN: 10582

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10326 AN: 67984

Other (OTH) AF: 0.144 AC: 304 AN: 2110

Alfa AF: 0.141 Hom.: 2653

Bravo AF: 0.104

Asia WGS AF: 0.0440 AC: 155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.82
PhyloP100		-1.4
PromoterAI		0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=297/3	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: rs4647603; hg19: chr4-185569730;