Genetic Variant NM_019896.4:c.50G>T (chr2-74958729-G-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3BA1

The NM_019896.4(POLE4):c.50G>T(p.Gly17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,513,020 control chromosomes in the GnomAD database, including 111,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.36 ( 10210 hom., cov: 33)

Exomes 𝑓: 0.38 ( 100798 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: Benign. The variant received -7 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

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>T	p.Gly17Val	missense	Exon 1 of 4	NP_063949.2
LOC105374809	NR_187875.1		n.148+3C>A		splice_region intron	N/A
LOC105374809	NR_187876.1		n.148+3C>A		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>T	p.Gly17Val	missense	Exon 1 of 4	ENSP00000420176.1	Q9NR33
POLE4	ENST00000871512.1		c.50G>T	p.Gly17Val	missense	Exon 1 of 4	ENSP00000541571.1
POLE4	ENST00000871513.1		c.50G>T	p.Gly17Val	missense	Exon 1 of 4	ENSP00000541572.1

Frequencies

GnomAD3 genomes

AF:

0.365

AC:

55384

AN:

151886

Hom.:

10207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.332

Gnomad AMI

AF:

0.439

Gnomad AMR

AF:

0.373

Gnomad ASJ

AF:

0.507

Gnomad EAS

AF:

0.428

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.256

Gnomad MID

AF:

0.548

Gnomad NFE

AF:

0.391

Gnomad OTH

AF:

0.380

GnomAD2 exomes

AF:

0.337

AC:

38503

AN:

114154

AF XY:

0.337

show subpopulations

Gnomad AFR exome

AF:

0.285

Gnomad AMR exome

AF:

0.285

Gnomad ASJ exome

AF:

0.492

Gnomad EAS exome

AF:

0.401

Gnomad FIN exome

AF:

0.268

Gnomad NFE exome

AF:

0.376

Gnomad OTH exome

AF:

0.393

GnomAD4 exome

AF:

0.382

AC:

519672

AN:

1361020

Hom.:

100798

Cov.:

AF XY:

0.380

AC XY:

254950

AN XY:

671294

show subpopulations

African (AFR)

AF:

0.329

AC:

9007

AN:

27346

American (AMR)

AF:

0.311

AC:

9064

AN:

29154

Ashkenazi Jewish (ASJ)

AF:

0.501

AC:

11809

AN:

23570

East Asian (EAS)

AF:

0.413

AC:

12883

AN:

31162

South Asian (SAS)

AF:

0.294

AC:

22407

AN:

76136

European-Finnish (FIN)

AF:

0.275

AC:

13296

AN:

48286

Middle Eastern (MID)

AF:

0.520

AC:

2846

AN:

5470

European-Non Finnish (NFE)

AF:

0.391

AC:

416455

AN:

1063798

Other (OTH)

AF:

0.390

AC:

21905

AN:

56098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

17241

34482

51723

68964

86205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13294

26588

39882

53176

66470

<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

AF:

0.364

AC:

55400

AN:

152000

Hom.:

10210

Cov.:

AF XY:

0.358

AC XY:

26609

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.331

AC:

13753

AN:

41504

American (AMR)

AF:

0.373

AC:

5704

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.507

AC:

1760

AN:

3468

East Asian (EAS)

AF:

0.427

AC:

2188

AN:

5126

South Asian (SAS)

AF:

0.292

AC:

1407

AN:

4818

European-Finnish (FIN)

AF:

0.256

AC:

2710

AN:

10600

Middle Eastern (MID)

AF:

0.558

AC:

163

AN:

292

European-Non Finnish (NFE)

AF:

0.391

AC:

26521

AN:

67882

Other (OTH)

AF:

0.377

AC:

795

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1796

3592

5389

7185

8981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.353

Hom.:

3706

Bravo

AF:

0.374

TwinsUK

AF:

0.389

AC:

1441

ALSPAC

AF:

0.405

AC:

1560

ESP6500AA

AF:

0.282

AC:

1078

ESP6500EA

AF:

0.347

AC:

2577

ExAC

AF:

0.204

AC:

13237

Asia WGS

AF:

0.339

AC:

1178

AN:

3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0049

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.099

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.53

MetaRNN

Benign

0.00042

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.90

PhyloP100

0.99

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.1

REVEL

Benign

0.049

Sift

Benign

0.23

Sift4G

Benign

0.35

Polyphen

0.47

Vest4

0.085

MPC

1.1

ClinPred

0.094

GERP RS

3.6

PromoterAI

0.33

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.079

gMVP

0.25

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.62

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.62

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over