rs532411

Variant names:

• chr3-121467575-G-A
• rs532411
• NM_199420.4:c.6911C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-121467575-G-A
• chr3-121467575-G-C
• chr3-121467575-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_199420.4(POLQ):​c.6911C>T​(p.Ala2304Val) variant causes a missense change. The variant allele was found at a frequency of 0.067 in 1,613,214 control chromosomes in the GnomAD database, including 4,717 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2304S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.098 (1064 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3653 hom.)
• Consequence: POLQ NM_199420.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.47
• Publications: 22 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010478795).
• BP6: Variant 3-121467575-G-A is Benign according to our data. Variant chr3-121467575-G-A is described in ClinVar as Benign. ClinVar VariationId is 3055919.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
POLQ	NM_199420.4	c.6911C>T	p.Ala2304Val	missense_variant	Exon 24 of 30	ENST00000264233.6	NP_955452.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLQ	ENST00000264233.6	c.6911C>T	p.Ala2304Val	missense_variant	Exon 24 of 30	1	NM_199420.4	ENSP00000264233.5
POLQ	ENST00000474243.1	n.412C>T		non_coding_transcript_exon_variant	Exon 4 of 6	5

Frequencies

GnomAD3 genomes AF: 0.0980 AC: 14910 AN: 152134 Hom.: 1059 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0626

Gnomad ASJ AF: 0.0786

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0593

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0955

GnomAD2 exomes AF: 0.0613 AC: 15382 AN: 250860 AF XY: 0.0569

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.0406

Gnomad ASJ exome AF: 0.0776

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0558

Gnomad NFE exome AF: 0.0702

Gnomad OTH exome AF: 0.0615

GnomAD4 exome AF: 0.0638 AC: 93152 AN: 1460962 Hom.: 3653 Cov.: 30 AF XY: 0.0619 AC XY: 44985 AN XY: 726844

African (AFR) AF: 0.205 AC: 6869 AN: 33452

American (AMR) AF: 0.0435 AC: 1943 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0784 AC: 2048 AN: 26118

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0134 AC: 1159 AN: 86216

European-Finnish (FIN) AF: 0.0580 AC: 3098 AN: 53410

Middle Eastern (MID) AF: 0.0652 AC: 376 AN: 5768

European-Non Finnish (NFE) AF: 0.0663 AC: 73706 AN: 1111262

Other (OTH) AF: 0.0655 AC: 3951 AN: 60354

GnomAD4 genome AF: 0.0981 AC: 14934 AN: 152252 Hom.: 1064 Cov.: 32 AF XY: 0.0952 AC XY: 7085 AN XY: 74450

African (AFR) AF: 0.195 AC: 8117 AN: 41522

American (AMR) AF: 0.0625 AC: 956 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0786 AC: 273 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4824

European-Finnish (FIN) AF: 0.0593 AC: 629 AN: 10608

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0687 AC: 4676 AN: 68018

Other (OTH) AF: 0.0945 AC: 200 AN: 2116

Alfa AF: 0.0744 Hom.: 1712

Bravo AF: 0.103

TwinsUK AF: 0.0685 AC: 254

ALSPAC AF: 0.0646 AC: 249

ESP6500AA AF: 0.201 AC: 887

ESP6500EA AF: 0.0638 AC: 549

ExAC AF: 0.0653 AC: 7927

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.0688

EpiControl AF: 0.0658

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

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	Benign	0.096
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0010	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;L
PhyloP100		4.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.0	.;N
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.10	T;T
Vest4		0.022
ClinPred		0.016	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.32
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs532411; hg19: chr3-121186422; COSMIC: COSV51752125;