chr12-132649027-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006231.4(POLE):​c.4051G>T​(p.Val1351Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,382 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1351I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

10
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.45
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
POLENM_006231.4 linkuse as main transcriptc.4051G>T p.Val1351Phe missense_variant 32/49 ENST00000320574.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.4051G>T p.Val1351Phe missense_variant 32/491 NM_006231.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461382
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727018
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Benign
-0.073
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
7.8
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D;.
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.42
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.028
D
MetaRNN
Uncertain
0.65
D;D
MetaSVM
Benign
-0.95
T
MutationAssessor
Uncertain
2.2
M;.
MutationTaster
Benign
0.72
N;N;N
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Benign
0.18
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
0.25
B;B
Vest4
0.45
MutPred
0.68
Gain of catalytic residue at R1346 (P = 0);.;
MVP
0.51
MPC
0.49
ClinPred
0.97
D
GERP RS
1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.37
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: chr12-133225613; COSMIC: COSV57681296; COSMIC: COSV57681296; API