12-132673167-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006231.4(POLE):​c.1470C>A​(p.Asp490Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,544 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 (★). Synonymous variant affecting the same amino acid position (i.e. D490D) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.307
Variant links:
Genes affected
POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkc.1470C>A p.Asp490Glu missense_variant 14/49 ENST00000320574.10 NP_006222.2 Q07864

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkc.1470C>A p.Asp490Glu missense_variant 14/491 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.93e-7
AC:
1
AN:
1443544
Hom.:
0
Cov.:
30
AF XY:
0.00000139
AC XY:
1
AN XY:
719296
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:
0.0000167
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 15, 2020This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces aspartic acid with glutamic acid at codon 490 of the POLE protein (p.Asp490Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
7.4
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.63
D;.
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.42
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.021
T
MetaRNN
Pathogenic
0.76
D;D
MetaSVM
Benign
-0.64
T
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.8
D;D
REVEL
Benign
0.29
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;D
Vest4
0.81
MutPred
0.41
Gain of catalytic residue at P486 (P = 0.0021);.;
MVP
0.37
MPC
0.75
ClinPred
0.99
D
GERP RS
1.7
Varity_R
0.71
gMVP
0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-133249753; API