rs3218634

chr3-121432965-G-Achr3-121432965-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_199420.4(POLQ):c.7612C>T(p.Leu2538Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2538V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLQ NM_199420.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLQ	NM_199420.4	c.7612C>T	p.Leu2538Phe	missense_variant	29/30	ENST00000264233.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLQ	ENST00000264233.6	c.7612C>T	p.Leu2538Phe	missense_variant	29/30	1	NM_199420.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459030 Hom.: 0 Cov.: 28 AF XY: 0.00000275 AC XY: 2 AN XY: 726012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.16	P
PrimateAI	Uncertain	0.71	T
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	.;D
Vest4		0.61
MutPred		0.58		.;Gain of sheet (P = 0.0221);
MVP		0.67
MPC		0.44
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.95
gMVP		0.53

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: rs3218634; hg19: chr3-121151812;