Variant chr2-74958692-G-C 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_019896.4(POLE4):c.13G>C(p.Ala5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000759 in 1,317,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. A5S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

POLE4
NM_019896.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54

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 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=0.14370304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLE4	NM_019896.4 linkuse as main transcript	c.13G>C	p.Ala5Pro	missense_variant	1/4	ENST00000483063.2
LOC105374809	XR_002959406.2 linkuse as main transcript	n.148+40C>G		intron_variant, non_coding_transcript_variant
LOC105374809	XR_007087109.1 linkuse as main transcript	n.148+40C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
POLE4	ENST00000483063.2 linkuse as main transcript	c.13G>C	p.Ala5Pro	missense_variant	1/4	1	NM_019896.4	P1
POLE4	ENST00000459636.5 linkuse as main transcript			upstream_gene_variant		3
POLE4	ENST00000485527.5 linkuse as main transcript			upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.59e-7

AC:

AN:

1317576

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

648344

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000185

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

Mar 23, 2022

The c.13G>C (p.A5P) alteration is located in exon 1 (coding exon 1) of the POLE4 gene. This alteration results from a G to C substitution at nucleotide position 13, causing the alanine (A) at amino acid position 5 to be replaced by a proline (P). 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

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0026

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.097

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.38

M_CAP

Benign

0.045

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

MutationTaster

Benign

0.90

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.3

REVEL

Benign

0.038

Sift

Benign

0.18

Sift4G

Uncertain

0.049

Polyphen

0.054

Vest4

0.28

MutPred

0.26

Gain of glycosylation at A5 (P = 0.0357);

MVP

0.32

MPC

0.84

ClinPred

0.84

GERP RS

4.5

Varity_R

0.21

gMVP

0.32

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over