3-121432371-G-A

Position:

• chr3-121432371-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_199420.4(POLQ):​c.7706C>T​(p.Ser2569Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLQ NM_199420.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLQ	NM_199420.4	c.7706C>T	p.Ser2569Phe	missense_variant	30/30	ENST00000264233.6	NP_955452.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLQ	ENST00000264233.6	c.7706C>T	p.Ser2569Phe	missense_variant	30/30	1	NM_199420.4	ENSP00000264233.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2024

The p.S2569F variant (also known as c.7706C>T), located in coding exon 30 of the POLQ gene, results from a C to T substitution at nucleotide position 7706. The serine at codon 2569 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.010	.;D
Sift4G	Benign	0.088	T;T
Polyphen		1.0	.;D
Vest4		0.59
MutPred		0.48		.;Loss of disorder (P = 0.0325);
MVP		0.86
MPC		0.43
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.84
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-121151218;