4-184657075-G-T

Variant names:

• chr4-184657075-G-T
• rs13108061
• NM_152683.4:c.-59-7G>T

Variant summary

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

The NM_152683.4(PRIMPOL):​c.-59-7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 1,201,306 control chromosomes in the GnomAD database, including 192,960 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.48 (18800 hom., cov: 33)
  • Exomes 𝑓: 0.57 (174160 hom.)
• Consequence: PRIMPOL NM_152683.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001474
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.539
• Publications: 8 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152683.4. 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.-59-7G>T		splice_region intron	N/A	NP_689896.1
	PRIMPOL	NM_001345891.2		c.-59-7G>T		splice_region intron	N/A	NP_001332820.1
	PRIMPOL	NM_001345892.2		c.-56-10G>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.-59-7G>T		splice_region intron	N/A	ENSP00000313816.6
	PRIMPOL	ENST00000512834.5	TSL:1	c.-59-7G>T		splice_region intron	N/A	ENSP00000425316.1
	PRIMPOL	ENST00000515774.5	TSL:1	c.-207-2265G>T		intron	N/A	ENSP00000421913.1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73129 AN: 151922 Hom.: 18801 Cov.: 33

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.481

GnomAD4 exome AF: 0.571 AC: 598726 AN: 1049266 Hom.: 174160 Cov.: 13 AF XY: 0.569 AC XY: 294001 AN XY: 517146

African (AFR) AF: 0.296 AC: 6497 AN: 21982

American (AMR) AF: 0.387 AC: 7469 AN: 19316

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 9738 AN: 16828

East Asian (EAS) AF: 0.332 AC: 10351 AN: 31154

South Asian (SAS) AF: 0.475 AC: 19422 AN: 40888

European-Finnish (FIN) AF: 0.583 AC: 23458 AN: 40256

Middle Eastern (MID) AF: 0.567 AC: 2603 AN: 4590

European-Non Finnish (NFE) AF: 0.597 AC: 495853 AN: 830950

Other (OTH) AF: 0.539 AC: 23335 AN: 43302

GnomAD4 genome AF: 0.481 AC: 73135 AN: 152040 Hom.: 18800 Cov.: 33 AF XY: 0.478 AC XY: 35541 AN XY: 74300

African (AFR) AF: 0.304 AC: 12630 AN: 41488

American (AMR) AF: 0.444 AC: 6781 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2044 AN: 3466

East Asian (EAS) AF: 0.292 AC: 1512 AN: 5184

South Asian (SAS) AF: 0.505 AC: 2435 AN: 4822

European-Finnish (FIN) AF: 0.588 AC: 6202 AN: 10544

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.586 AC: 39830 AN: 67970

Other (OTH) AF: 0.480 AC: 1011 AN: 2106

Alfa AF: 0.520 Hom.: 11736

Bravo AF: 0.461

Asia WGS AF: 0.407 AC: 1414 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.0
DANN	Benign	0.65
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0040
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: rs13108061; hg19: chr4-185578229; COSMIC: COSV59249386;