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

Variant summary

Our verdict is Benign. The variant received -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

Publications

11 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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

GnomAD2 exomes

AF:

0.00933

AC:

2336

AN:

250482

AF XY:

0.00917

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 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

African (AFR)

AF:

0.00120

AC:

AN:

33428

American (AMR)

AF:

0.00437

AC:

195

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00793

AC:

207

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.000546

AC:

AN:

86076

European-Finnish (FIN)

AF:

0.0228

AC:

1216

AN:

53378

Middle Eastern (MID)

AF:

0.00313

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0121

AC:

13453

AN:

1110604

Other (OTH)

AF:

0.00879

AC:

530

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

656

1312

1967

2623

3279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00928

AC:

1413

AN:

152336

Hom.:

Cov.:

AF XY:

0.00980

AC XY:

730

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

41594

American (AMR)

AF:

0.00523

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0286

AC:

303

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0130

AC:

885

AN:

68024

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

150

226

301

376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0109

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

(source)

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

PhyloP100

7.4

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

Mutation Taster

=193/107

polymorphism

(source)

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

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4-184661800-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over