chr4-184650403-C-T

Variant names:

• chr4-184650403-C-T
• rs12108497
• NM_152683.4:c.-138+495C>T

Variant summary

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

The NM_001345891.2(PRIMPOL):​c.-138+495C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,054 control chromosomes in the GnomAD database, including 7,954 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 0.31 (7954 hom., cov: 33)
• Consequence: PRIMPOL NM_001345891.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.757
• Publications: 47 publications found

Genes affected

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]

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]

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 (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001345891.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRIMPOL	NM_152683.4	MANE Select	c.-138+495C>T		intron	N/A	NP_689896.1
	PRIMPOL	NM_001345891.2		c.-138+495C>T		intron	N/A	NP_001332820.1
	PRIMPOL	NM_001345892.2		c.-135+495C>T		intron	N/A	NP_001332821.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRIMPOL	ENST00000314970.11	TSL:1 MANE Select	c.-138+495C>T		intron	N/A	ENSP00000313816.6
	PRIMPOL	ENST00000512834.5	TSL:1	c.-138+495C>T		intron	N/A	ENSP00000425316.1
	PRIMPOL	ENST00000515774.5	TSL:1	c.-286+495C>T		intron	N/A	ENSP00000421913.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46664 AN: 151936 Hom.: 7952 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.342

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

GnomAD4 genome AF: 0.307 AC: 46687 AN: 152054 Hom.: 7954 Cov.: 33 AF XY: 0.316 AC XY: 23527 AN XY: 74344

African (AFR) AF: 0.210 AC: 8731 AN: 41482

American (AMR) AF: 0.433 AC: 6625 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1186 AN: 3466

East Asian (EAS) AF: 0.704 AC: 3636 AN: 5164

South Asian (SAS) AF: 0.397 AC: 1917 AN: 4826

European-Finnish (FIN) AF: 0.330 AC: 3483 AN: 10564

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20021 AN: 67948

Other (OTH) AF: 0.342 AC: 724 AN: 2116

Alfa AF: 0.303 Hom.: 24802

Bravo AF: 0.315

Asia WGS AF: 0.508 AC: 1767 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	2.7
DANN	Benign	0.79
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12108497; hg19: chr4-185571557;