12-132643265-T-C

Variant names:

• chr12-132643265-T-C
• NM_006231.4:c.4510A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006231.4(POLE):​c.4510A>G​(p.Ile1504Val) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1504F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.527

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]

ACMG classification

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=0.08957508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.4510A>G	p.Ile1504Val	missense_variant	Exon 35 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.4510A>G	p.Ile1504Val	missense_variant	Exon 35 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.2
DANN	Benign	0.38
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.090	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.078
Sift	Benign	0.66	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.0	B;B
Vest4		0.097
MutPred		0.43		Gain of catalytic residue at R1509 (P = 0.0021);.;
MVP		0.16
MPC		0.16
ClinPred		0.041	T
GERP RS		-0.94
Varity_R		0.014
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-133219851;