rs4647603

Variant names:

• chr4-184648576-C-G
• rs4647603
• NM_004346.4:c.-127G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-184648576-C-G
• chr4-184648576-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004346.4(CASP3):​c.-127G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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>C		5_prime_UTR	Exon 2 of 8	NP_004337.2
	CASP3	NM_001354777.2		c.-89G>C		5_prime_UTR	Exon 2 of 8	NP_001341706.1	P42574
	CASP3	NM_001354780.2		c.-201G>C		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>C		5_prime_UTR	Exon 2 of 8	ENSP00000311032.4	P42574
	CASP3	ENST00000393585.6	TSL:1	c.-319G>C		5_prime_UTR	Exon 1 of 7	ENSP00000377210.2	A8MVM1
	CASP3	ENST00000523916.5	TSL:1	c.-16+819G>C		intron	N/A	ENSP00000428929.1	P42574

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 9824 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 5250

African (AFR) AF: 0.00 AC: 0 AN: 218

American (AMR) AF: 0.00 AC: 0 AN: 134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 306

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 68

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 60

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 6178

Other (OTH) AF: 0.00 AC: 0 AN: 548

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 2653

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.84
DANN	Benign	0.62
PhyloP100		-1.4
PromoterAI		0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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;