Genetic Variant POLQ:p.Leu2538Val (chr3-121432965-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_199420.4(POLQ):c.7612C>G(p.Leu2538Val) variant causes a missense change. The variant allele was found at a frequency of 0.0668 in 1,609,960 control chromosomes in the GnomAD database, including 4,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.098 ( 1051 hom., cov: 32)

Exomes 𝑓: 0.064 ( 3645 hom. )

Consequence

POLQ
NM_199420.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 6.16

Publications

21 publications found

Variant links:

Genes affected

POLQ (HGNC:9186): (DNA polymerase theta) Enables catalytic activity, acting on DNA; chromatin binding activity; and identical protein binding activity. Involved in DNA repair; negative regulation of double-strand break repair via homologous recombination; and protein homooligomerization. Located in Golgi apparatus; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

POLQ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024261475).

BP6

Variant 3-121432965-G-C is Benign according to our data. Variant chr3-121432965-G-C is described in ClinVar as Benign. ClinVar VariationId is 3056748.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLQ	NM_199420.4 link	c.7612C>G	p.Leu2538Val	missense_variant	Exon 29 of 30	ENST00000264233.6	NP_955452.3	O75417-1Q59EE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLQ	ENST00000264233.6 link	c.7612C>G	p.Leu2538Val	missense_variant	Exon 29 of 30	1	NM_199420.4	ENSP00000264233.5		O75417-1

Frequencies

GnomAD3 genomes

AF:

0.0976

AC:

14845

AN:

152116

Hom.:

1046

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0627

Gnomad ASJ

AF:

0.0787

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0592

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0690

Gnomad OTH

AF:

0.0964

GnomAD2 exomes

AF:

0.0618

AC:

15506

AN:

251036

AF XY:

0.0573

show subpopulations

Gnomad AFR exome

AF:

0.200

Gnomad AMR exome

AF:

0.0410

Gnomad ASJ exome

AF:

0.0785

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0560

Gnomad NFE exome

AF:

0.0711

Gnomad OTH exome

AF:

0.0619

GnomAD4 exome

AF:

0.0635

AC:

92622

AN:

1457726

Hom.:

3645

Cov.:

AF XY:

0.0617

AC XY:

44740

AN XY:

725412

show subpopulations

African (AFR)

AF:

0.202

AC:

6732

AN:

33326

American (AMR)

AF:

0.0435

AC:

1943

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0785

AC:

2049

AN:

26112

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39674

South Asian (SAS)

AF:

0.0135

AC:

1166

AN:

86204

European-Finnish (FIN)

AF:

0.0582

AC:

3106

AN:

53406

Middle Eastern (MID)

AF:

0.0648

AC:

373

AN:

5760

European-Non Finnish (NFE)

AF:

0.0661

AC:

73312

AN:

1108280

Other (OTH)

AF:

0.0654

AC:

3939

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

3906

7812

11719

15625

19531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2652

5304

7956

10608

13260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0977

AC:

14870

AN:

152234

Hom.:

1051

Cov.:

AF XY:

0.0946

AC XY:

7041

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.193

AC:

8033

AN:

41520

American (AMR)

AF:

0.0625

AC:

956

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0787

AC:

273

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0108

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0592

AC:

628

AN:

10606

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0690

AC:

4695

AN:

68016

Other (OTH)

AF:

0.0954

AC:

201

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

660

1320

1979

2639

3299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0725

Hom.:

363

Bravo

AF:

0.103

TwinsUK

AF:

0.0688

AC:

255

ALSPAC

AF:

0.0651

AC:

251

ESP6500AA

AF:

0.199

AC:

878

ESP6500EA

AF:

0.0636

AC:

547

ExAC

AF:

0.0656

AC:

7970

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0695

EpiControl

AF:

0.0661

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

POLQ-related disorder

Benign:1

Oct 28, 2019

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

Uncertain

0.45

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.49

.;N

PhyloP100

6.2

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.3

.;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.0040

.;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

.;D

Vest4

0.26

MPC

0.42

ClinPred

0.021

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.84

gMVP

0.39

Mutation Taster

=85/15

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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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