Variant 2-74958729-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The ENST00000483063.2(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

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

Exomes 𝑓: 0.38 ( 100798 hom. )

Consequence

POLE4
ENST00000483063.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.995

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:

LOC105374809 (HGNC:):

LOC105374809 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLE4	NM_019896.4 linkuse as main transcript	c.50G>T	p.Gly17Val	missense_variant	1/4	ENST00000483063.2	NP_063949.2
LOC105374809	XR_002959406.2 linkuse as main transcript	n.148+3C>A		splice_donor_region_variant, intron_variant, non_coding_transcript_variant
LOC105374809	XR_007087109.1 linkuse as main transcript	n.148+3C>A		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
POLE4	ENST00000483063.2 linkuse as main transcript	c.50G>T	p.Gly17Val	missense_variant	1/4	1	NM_019896.4	ENSP00000420176	P1
POLE4	ENST00000459636.5 linkuse as main transcript	n.24G>T		non_coding_transcript_exon_variant	1/4	3
POLE4	ENST00000485527.5 linkuse as main transcript	n.25G>T		non_coding_transcript_exon_variant	1/3	2

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

GnomAD3 exomes

AF:

0.337

AC:

38503

AN:

114154

Hom.:

6999

AF XY:

0.337

AC XY:

21101

AN XY:

62528

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 SAS exome

AF:

0.282

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

Gnomad4 AFR exome

AF:

0.329

Gnomad4 AMR exome

AF:

0.311

Gnomad4 ASJ exome

AF:

0.501

Gnomad4 EAS exome

AF:

0.413

Gnomad4 SAS exome

AF:

0.294

Gnomad4 FIN exome

AF:

0.275

Gnomad4 NFE exome

AF:

0.391

Gnomad4 OTH exome

AF:

0.390

GnomAD4 genome

AF:

0.364

AC:

55400

AN:

152000

Hom.:

10210

Cov.:

AF XY:

0.358

AC XY:

26609

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.331

Gnomad4 AMR

AF:

0.373

Gnomad4 ASJ

AF:

0.507

Gnomad4 EAS

AF:

0.427

Gnomad4 SAS

AF:

0.292

Gnomad4 FIN

AF:

0.256

Gnomad4 NFE

AF:

0.391

Gnomad4 OTH

AF:

0.377

Alfa

AF:

0.350

Hom.:

3340

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

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

MutationTaster

Benign

0.000011

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.079

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over