Genetic Variant PRIMPOL:p.Val102Ala (chr4-184661800-T-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_152683.4(PRIMPOL):c.305T>C(p.Val102Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,612,282 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0093 ( 15 hom., cov: 33)

Exomes 𝑓: 0.011 ( 112 hom. )

Consequence

PRIMPOL
NM_152683.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.39

Variant links:

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]

PRIMPOL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015947789).

BP6

Variant 4-184661800-T-C is Benign according to our data. Variant chr4-184661800-T-C is described in ClinVar as [Benign]. Clinvar id is 3350436.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 1413 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRIMPOL	NM_152683.4 link	c.305T>C	p.Val102Ala	missense_variant	Exon 5 of 14	ENST00000314970.11	NP_689896.1	Q96LW4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRIMPOL	ENST00000314970.11 link	c.305T>C	p.Val102Ala	missense_variant	Exon 5 of 14	1	NM_152683.4	ENSP00000313816.6		Q96LW4-1

Frequencies

GnomAD3 genomes

AF:

0.00929

AC:

1414

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00178

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00524

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0286

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.00764

GnomAD3 exomes

AF:

0.00933

AC:

2336

AN:

250482

Hom.:

AF XY:

0.00917

AC XY:

1242

AN XY:

135430

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.00419

Gnomad ASJ exome

AF:

0.00716

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000493

Gnomad FIN exome

AF:

0.0249

Gnomad NFE exome

AF:

0.0131

Gnomad OTH exome

AF:

0.00917

GnomAD4 exome

AF:

0.0108

AC:

15706

AN:

1459946

Hom.:

112

Cov.:

AF XY:

0.0104

AC XY:

7583

AN XY:

726386

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.00437

Gnomad4 ASJ exome

AF:

0.00793

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000546

Gnomad4 FIN exome

AF:

0.0228

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00879

GnomAD4 genome

AF:

0.00928

AC:

1413

AN:

152336

Hom.:

Cov.:

AF XY:

0.00980

AC XY:

730

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.00523

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0286

Gnomad4 NFE

AF:

0.0130

Gnomad4 OTH

AF:

0.00756

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.00724

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0116

AC:

100

ExAC

AF:

0.00934

AC:

1134

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PRIMPOL-related disorder

Benign:1

May 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

.;T;T

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.5

M;M;M

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.87

MVP

0.63

MPC

0.16

ClinPred

0.026

GERP RS

5.8

Varity_R

0.60

gMVP

0.64

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over