Genetic Variant PRIMPOL:p.Thr82Ala (chr4-184659403-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152683.4(PRIMPOL):c.244A>G(p.Thr82Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,613,878 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 175 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 170 hom. )

Consequence

PRIMPOL
NM_152683.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.02

Publications

5 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032479465).

BP6

Variant 4-184659403-A-G is Benign according to our data. Variant chr4-184659403-A-G is described in ClinVar as [Benign]. Clinvar id is 785110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRIMPOL	NM_152683.4 link	c.244A>G	p.Thr82Ala	missense_variant	Exon 4 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.244A>G	p.Thr82Ala	missense_variant	Exon 4 of 14	1	NM_152683.4	ENSP00000313816.6		Q96LW4-1

Frequencies

GnomAD3 genomes

AF:

0.0257

AC:

3905

AN:

152198

Hom.:

175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.00724

AC:

1821

AN:

251410

AF XY:

0.00548

show subpopulations

Gnomad AFR exome

AF:

0.0960

Gnomad AMR exome

AF:

0.00471

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00281

AC:

4100

AN:

1461562

Hom.:

170

Cov.:

AF XY:

0.00246

AC XY:

1792

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.0934

AC:

3125

AN:

33446

American (AMR)

AF:

0.00479

AC:

214

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00356

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.000220

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000252

AC:

280

AN:

1111798

Other (OTH)

AF:

0.00566

AC:

342

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

180

360

540

720

900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0257

AC:

3915

AN:

152316

Hom.:

175

Cov.:

AF XY:

0.0249

AC XY:

1851

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0892

AC:

3708

AN:

41562

American (AMR)

AF:

0.00876

AC:

134

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68028

Other (OTH)

AF:

0.0198

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

191

382

574

765

956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00918

Hom.:

105

Bravo

AF:

0.0292

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0962

AC:

424

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00903

AC:

1097

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

T;T;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

.;T;D

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.2

M;M;M

PhyloP100

2.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.016

D;D;D

Sift4G

Benign

0.090

T;T;D

Polyphen

0.93

P;P;.

Vest4

0.46

MVP

0.38

MPC

0.12

ClinPred

0.068

GERP RS

4.3

Varity_R

0.27

gMVP

0.57

Mutation Taster

=295/5

polymorphism (auto)

(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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4-184659403-A-G

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