chr12-132687313-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_006231.4(POLE):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

POLE
NM_006231.4 start_lost

Scores

4
3
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.991
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_006231.4 (POLE) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkuse as main transcriptc.3G>C p.Met1? start_lost 1/49 ENST00000320574.10 NP_006222.2 Q07864

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.3G>C p.Met1? start_lost 1/491 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 26, 2017The p.M1? variant (also known as c.3G>C), located in coding exon 1 of the POLE gene, results from a G to C substitution at nucleotide position 3. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however there is an alternate in-frame methionine 43 amino acids from the initiation site. As neither this specific alteration nor loss-of-function as a mechanism of pathogenicity have been well-described in the POLE gene, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
20
DANN
Benign
0.95
DEOGEN2
Benign
0.12
T;.
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.041
N
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Benign
-0.99
T
PROVEAN
Benign
-2.0
N;N
REVEL
Benign
0.27
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.0
B;B
Vest4
0.71
MutPred
0.88
Gain of catalytic residue at R4 (P = 0.0169);Gain of catalytic residue at R4 (P = 0.0169);
MVP
0.32
ClinPred
0.53
D
GERP RS
2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.61

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: rs1555231433; hg19: chr12-133263899; API