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

Variant summary

Our verdict is Benign. Variant got -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

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 made for transcript

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.0618

AC:

15506

AN:

251036

Hom.:

728

AF XY:

0.0573

AC XY:

7768

AN XY:

135674

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 SAS exome

AF:

0.0131

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

Gnomad4 AFR exome

AF:

0.202

Gnomad4 AMR exome

AF:

0.0435

Gnomad4 ASJ exome

AF:

0.0785

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0135

Gnomad4 FIN exome

AF:

0.0582

Gnomad4 NFE exome

AF:

0.0661

Gnomad4 OTH exome

AF:

0.0654

GnomAD4 genome

AF:

0.0977

AC:

14870

AN:

152234

Hom.:

1051

Cov.:

AF XY:

0.0946

AC XY:

7041

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.193

Gnomad4 AMR

AF:

0.0625

Gnomad4 ASJ

AF:

0.0787

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0108

Gnomad4 FIN

AF:

0.0592

Gnomad4 NFE

AF:

0.0690

Gnomad4 OTH

AF:

0.0954

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

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

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

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