Genetic Variant POLE4:p.Gly17Glu (chr2-74958729-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019896.4(POLE4):c.50G>A(p.Gly17Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000734 in 1,361,626 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. G17V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

POLE4
NM_019896.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.995

Publications

52 publications found

Variant links:

Genes affected

POLE4 (HGNC:18755): (DNA polymerase epsilon 4, accessory subunit) POLE4 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]

POLE4 links:

ENSG00000309281 (HGNC:):

ENSG00000309281 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.070767015).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019896.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLE4	NM_019896.4	MANE Select	c.50G>A	p.Gly17Glu	missense	Exon 1 of 4	NP_063949.2
LOC105374809	NR_187875.1		n.148+3C>T		splice_region intron	N/A
LOC105374809	NR_187876.1		n.148+3C>T		splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLE4	ENST00000483063.2	TSL:1 MANE Select	c.50G>A	p.Gly17Glu	missense	Exon 1 of 4	ENSP00000420176.1	Q9NR33
POLE4	ENST00000871512.1		c.50G>A	p.Gly17Glu	missense	Exon 1 of 4	ENSP00000541571.1
POLE4	ENST00000871513.1		c.50G>A	p.Gly17Glu	missense	Exon 1 of 4	ENSP00000541572.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000876

AC:

AN:

114154

AF XY:

0.0000160

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:

0.0000231

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000734

AC:

AN:

1361626

Hom.:

Cov.:

AF XY:

0.00000596

AC XY:

AN XY:

671644

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27354

American (AMR)

AF:

0.00

AC:

AN:

29216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23608

East Asian (EAS)

AF:

0.00

AC:

AN:

31178

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.00000846

AC:

AN:

1064176

Other (OTH)

AF:

0.00

AC:

AN:

56128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

3706

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.00056

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.48

M_CAP

Benign

0.029

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

0.99

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.010

REVEL

Benign

0.069

Sift

Benign

0.30

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.13

MutPred

0.12

Loss of catalytic residue at G17 (P = 0.0746)

MVP

0.41

MPC

1.1

ClinPred

0.39

GERP RS

3.6

PromoterAI

0.14

Neutral

(source)

Varity_R

0.043

gMVP

0.21

Mutation Taster

=89/11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over