rs1241114520

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000320574.10(POLE):ā€‹c.46G>Cā€‹(p.Asp16His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D16A) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Failed GnomAD Quality Control

Consequence

POLE
ENST00000320574.10 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21158955).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkuse as main transcriptc.46G>C p.Asp16His missense_variant 1/49 ENST00000320574.10 NP_006222.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.46G>C p.Asp16His missense_variant 1/491 NM_006231.4 ENSP00000322570 P1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
1
AN:
151496
Hom.:
0
Cov.:
33
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000660
AC:
1
AN:
151496
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
73974
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00

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), LabcorpSep 02, 2017In 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. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with POLE-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces aspartic acid with histidine at codon 16 of the POLE protein (p.Asp16His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.069
T;.
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.71
T;T
M_CAP
Pathogenic
0.60
D
MetaRNN
Benign
0.21
T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
1.0
L;.
MutationTaster
Benign
0.93
D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.041
Sift
Benign
0.12
T;T
Sift4G
Uncertain
0.053
T;T
Polyphen
0.23
B;B
Vest4
0.23
MutPred
0.23
Gain of catalytic residue at E18 (P = 0.0112);Gain of catalytic residue at E18 (P = 0.0112);
MVP
0.37
MPC
0.24
ClinPred
0.19
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.089
gMVP
0.37

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.

Other links and lift over

dbSNP: rs1241114520; hg19: chr12-133263856; API