3-121432343-T-C

Position:

• chr3-121432343-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199420.4(POLQ):​c.7734A>G​(p.Ile2578Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLQ NM_199420.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.116

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14758778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLQ	NM_199420.4	c.7734A>G	p.Ile2578Met	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.7734A>G	p.Ile2578Met	missense_variant	30/30	1	NM_199420.4	ENSP00000264233.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 16, 2022

The p.I2578M variant (also known as c.7734A>G), located in coding exon 30 of the POLQ gene, results from an A to G substitution at nucleotide position 7734. The isoleucine at codon 2578 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Uncertain	0.46	.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	.;N
REVEL	Benign	0.28
Sift	Benign	0.21	.;T
Sift4G	Benign	0.18	T;T
Polyphen		0.25	.;B
Vest4		0.24
MutPred		0.70		.;Gain of disorder (P = 0.0321);
MVP		0.33
MPC		0.25
ClinPred		0.36	T
GERP RS		-6.6
Varity_R		0.28
gMVP		0.51

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: chr3-121151190;