Genetic Variant NM_017443.5:c.281G>A (chr9-113408974-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017443.5(POLE3):c.281G>A(p.Arg94Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. R94L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

POLE3
NM_017443.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83

Publications

0 publications found

Variant links:

Genes affected

POLE3 (HGNC:13546): (DNA polymerase epsilon 3, accessory subunit) POLE3 is a histone-fold protein that interacts with other histone-fold proteins to bind DNA in a sequence-independent manner. These histone-fold protein dimers combine within larger enzymatic complexes for DNA transcription, replication, and packaging.[supplied by OMIM, Apr 2004]

POLE3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050623626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE3	NM_017443.5 link	c.281G>A	p.Arg94Gln	missense_variant	Exon 5 of 5	ENST00000374171.5	NP_059139.3	Q9NRF9A0A024R829
POLE3	NM_001278255.1 link	c.281G>A	p.Arg94Gln	missense_variant	Exon 5 of 5		NP_001265184.1	Q9NRF9A0A024R829
POLE3	NM_001433719.1 link	c.281G>A	p.Arg94Gln	missense_variant	Exon 4 of 4		NP_001420648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POLE3	ENST00000374171.5 link	c.281G>A	p.Arg94Gln	missense_variant	Exon 5 of 5	2	NM_017443.5	ENSP00000363286.4	Q9NRF9
POLE3	ENST00000374169.7 link	c.281G>A	p.Arg94Gln	missense_variant	Exon 4 of 4	1		ENSP00000363284.3	Q9NRF9
POLE3	ENST00000475080.1 link	n.425G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
POLE3	ENST00000479871.1 link	n.657G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249222

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461550

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53276

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.85

.;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.085

N;N

PhyloP100

1.8

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.042

Sift

Benign

0.39

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.041

B;B

Vest4

0.10

MutPred

0.25

Loss of MoRF binding (P = 0.0352);Loss of MoRF binding (P = 0.0352);

MVP

0.22

MPC

0.30

ClinPred

0.086

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.077

gMVP

0.084

Mutation Taster

=86/14

polymorphism

(source)

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

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NM_017443.5:c.281G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over