9-113409651-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_017443.5(POLE3):c.230A>C(p.Glu77Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E77V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

POLE3
NM_017443.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.29

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE3	NM_017443.5 link	c.230A>C	p.Glu77Ala	missense_variant	Exon 4 of 5	ENST00000374171.5	NP_059139.3	Q9NRF9A0A024R829
POLE3	NM_001278255.1 link	c.230A>C	p.Glu77Ala	missense_variant	Exon 4 of 5		NP_001265184.1	Q9NRF9A0A024R829
POLE3	NM_001433719.1 link	c.230A>C	p.Glu77Ala	missense_variant	Exon 3 of 4		NP_001420648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POLE3	ENST00000374171.5 link	c.230A>C	p.Glu77Ala	missense_variant	Exon 4 of 5	2	NM_017443.5	ENSP00000363286.4	Q9NRF9
POLE3	ENST00000374169.7 link	c.230A>C	p.Glu77Ala	missense_variant	Exon 3 of 4	1		ENSP00000363284.3	Q9NRF9
POLE3	ENST00000475080.1 link	n.374A>C		non_coding_transcript_exon_variant	Exon 2 of 3	2
POLE3	ENST00000479871.1 link	n.606A>C		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251456

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00000342

AC:

AN:

1460858

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33448

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111154

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000394

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.230A>C (p.E77A) alteration is located in exon 4 (coding exon 3) of the POLE3 gene. This alteration results from a A to C substitution at nucleotide position 230, causing the glutamic acid (E) at amino acid position 77 to be replaced by an alanine (A). 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

Pathogenic

0.90

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

.;D

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Benign

-0.83

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

7.3

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.040

D;D

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.75

Loss of disorder (P = 0.0845);Loss of disorder (P = 0.0845);

MVP

0.39

MPC

0.93

ClinPred

0.98

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.64

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

9-113409651-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over