rs487848

chr3-121510113-G-Achr3-121510113-G-Cchr3-121510113-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_199420.4(POLQ):c.1742C>T(p.Ala581Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.067 in 1,613,052 control chromosomes in the GnomAD database, including 4,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A581T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.098 (1068 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3658 hom.)
• Consequence: POLQ NM_199420.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.59

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018025637).
• BP6: Variant 3-121510113-G-A is Benign according to our data. Variant chr3-121510113-G-A is described in ClinVar as [Benign]. Clinvar id is 3056620.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLQ	NM_199420.4	c.1742C>T	p.Ala581Val	missense_variant	11/30	ENST00000264233.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLQ	ENST00000264233.6	c.1742C>T	p.Ala581Val	missense_variant	11/30	1	NM_199420.4	P1

Frequencies

GnomAD3 genomes AF: 0.0982 AC: 14914 AN: 151946 Hom.: 1063 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0626

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0594

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0951

GnomAD3 exomes AF: 0.0617 AC: 15505 AN: 251438 Hom.: 738 AF XY: 0.0572 AC XY: 7771 AN XY: 135878

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.0784

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0131

Gnomad FIN exome AF: 0.0559

Gnomad NFE exome AF: 0.0705

Gnomad OTH exome AF: 0.0623

GnomAD4 exome AF: 0.0637 AC: 93100 AN: 1460988 Hom.: 3658 Cov.: 32 AF XY: 0.0619 AC XY: 44974 AN XY: 726858

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.0437

Gnomad4 ASJ exome AF: 0.0786

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0580

Gnomad4 NFE exome AF: 0.0663

Gnomad4 OTH exome AF: 0.0656

GnomAD4 genome AF: 0.0982 AC: 14939 AN: 152064 Hom.: 1068 Cov.: 32 AF XY: 0.0954 AC XY: 7091 AN XY: 74318

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.0625

Gnomad4 ASJ AF: 0.0784

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.0594

Gnomad4 NFE AF: 0.0689

Gnomad4 OTH AF: 0.0941

Alfa AF: 0.0725 Hom.: 1084

Bravo AF: 0.103

TwinsUK AF: 0.0688 AC: 255

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.202 AC: 888

ESP6500EA AF: 0.0637 AC: 548

ExAC AF: 0.0654 AC: 7934

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0695

EpiControl AF: 0.0660

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

POLQ-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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	Benign	0.18
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.0041	P
PrimateAI	Benign	0.40	T
Sift4G	Uncertain	0.046	D;T
Polyphen		0.47	.;P
Vest4		0.12
MPC		0.12
ClinPred		0.060	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.45

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

Other links and lift over

dbSNP: rs487848; hg19: chr3-121228960; COSMIC: COSV51750924;