rs374022997

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006231.4(POLE):​c.5633G>T​(p.Arg1878Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

POLE
NM_006231.4 missense

Scores

4
4
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.97
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkuse as main transcriptc.5633G>T p.Arg1878Leu missense_variant 41/49 ENST00000320574.10 NP_006222.2
POLEXM_011534795.4 linkuse as main transcriptc.5633G>T p.Arg1878Leu missense_variant 41/48 XP_011533097.1
POLEXM_011534797.4 linkuse as main transcriptc.4712G>T p.Arg1571Leu missense_variant 33/40 XP_011533099.1
POLEXM_011534802.4 linkuse as main transcriptc.2621G>T p.Arg874Leu missense_variant 17/24 XP_011533104.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.5633G>T p.Arg1878Leu missense_variant 41/491 NM_006231.4 ENSP00000322570 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T;.
Eigen
Benign
0.10
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Benign
0.014
T
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
2.0
M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Benign
0.24
Sift
Benign
0.18
T;T
Sift4G
Benign
0.78
T;T
Polyphen
0.25
B;.
Vest4
0.81
MutPred
0.69
Loss of methylation at K1877 (P = 0.0329);.;
MVP
0.49
MPC
0.32
ClinPred
0.99
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.44
gMVP
0.53

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: chr12-133214645; API