Variant 9-113408864-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017443.5(POLE3):c.391G>A(p.Glu131Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

POLE3
NM_017443.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.72

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 made for transcript

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=0.15532613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLE3	NM_017443.5 linkuse as main transcript	c.391G>A	p.Glu131Lys	missense_variant	5/5	ENST00000374171.5	NP_059139.3
POLE3	NM_001278255.1 linkuse as main transcript	c.391G>A	p.Glu131Lys	missense_variant	5/5		NP_001265184.1
POLE3	NR_027261.2 linkuse as main transcript	n.472G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
POLE3	ENST00000374171.5 linkuse as main transcript	c.391G>A	p.Glu131Lys	missense_variant	5/5	2	NM_017443.5	ENSP00000363286	P1
POLE3	ENST00000374169.7 linkuse as main transcript	c.391G>A	p.Glu131Lys	missense_variant	4/4	1		ENSP00000363284	P1
POLE3	ENST00000479871.1 linkuse as main transcript	n.767G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460840

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.391G>A (p.E131K) alteration is located in exon 5 (coding exon 4) of the POLE3 gene. This alteration results from a G to A substitution at nucleotide position 391, causing the glutamic acid (E) at amino acid position 131 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

.;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.86

N;N

REVEL

Benign

0.035

Sift

Benign

0.52

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.082

B;B

Vest4

0.22

MutPred

0.25

Gain of ubiquitination at E131 (P = 0.0109);Gain of ubiquitination at E131 (P = 0.0109);

MVP

0.41

MPC

0.29

ClinPred

0.57

GERP RS

4.8

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.16

gMVP

0.15

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over