chr3-121510113-G-A

Variant names:

• chr3-121510113-G-A
• rs487848
• NM_199420.4:c.1742C>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.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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A581S) 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 no assertion criteria provided B:1
• Conservation: PhyloP100: 7.59
• Publications: 20 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=0.0018025637).
• BP6: Variant 3-121510113-G-A is Benign according to our data. Variant chr3-121510113-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056620.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199420.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLQ	NM_199420.4	MANE Select	c.1742C>T	p.Ala581Val	missense	Exon 11 of 30	NP_955452.3	O75417-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLQ	ENST00000264233.6	TSL:1 MANE Select	c.1742C>T	p.Ala581Val	missense	Exon 11 of 30	ENSP00000264233.5	O75417-1
	POLQ	ENST00000932951.1		c.1742C>T	p.Ala581Val	missense	Exon 11 of 30	ENSP00000603010.1
	POLQ	ENST00000932953.1		c.1826C>T	p.Ala609Val	missense	Exon 12 of 30	ENSP00000603012.1

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

GnomAD2 exomes AF: 0.0617 AC: 15505 AN: 251438 AF XY: 0.0572

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 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

African (AFR) AF: 0.205 AC: 6868 AN: 33446

American (AMR) AF: 0.0437 AC: 1955 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0786 AC: 2055 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0135 AC: 1168 AN: 86250

European-Finnish (FIN) AF: 0.0580 AC: 3099 AN: 53418

Middle Eastern (MID) AF: 0.0652 AC: 376 AN: 5766

European-Non Finnish (NFE) AF: 0.0663 AC: 73620 AN: 1111194

Other (OTH) AF: 0.0656 AC: 3957 AN: 60362

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

African (AFR) AF: 0.196 AC: 8121 AN: 41440

American (AMR) AF: 0.0625 AC: 955 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0784 AC: 272 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4822

European-Finnish (FIN) AF: 0.0594 AC: 628 AN: 10576

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

European-Non Finnish (NFE) AF: 0.0689 AC: 4682 AN: 67982

Other (OTH) AF: 0.0941 AC: 198 AN: 2104

Alfa AF: 0.0771 Hom.: 2628

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	POLQ-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.090	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.6
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.14
Sift	Benign	0.15	T
Sift4G	Uncertain	0.046	D
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
Mutation Taster		=90/10	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: rs487848; hg19: chr3-121228960; COSMIC: COSV51750924;