rs5744761

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006231.4(POLE):​c.1226+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,600,170 control chromosomes in the GnomAD database, including 2,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 547 hom., cov: 32)
Exomes 𝑓: 0.047 ( 2322 hom. )

Consequence

POLE
NM_006231.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.30

Publications

9 publications found
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]
POLE Gene-Disease associations (from GenCC):
  • POLE-related polyposis and colorectal cancer syndrome
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • colorectal cancer, susceptibility to, 12
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • facial dysmorphism-immunodeficiency-livedo-short stature syndrome
    Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency
    Inheritance: AR Classification: STRONG Submitted by: G2P
  • IMAGe syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Polymerase proofreading-related adenomatous polyposis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
Variant 12-132675353-G-A is Benign according to our data. Variant chr12-132675353-G-A is described in CliVar as Benign. Clinvar id is 676492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132675353-G-A is described in CliVar as Benign. Clinvar id is 676492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132675353-G-A is described in CliVar as Benign. Clinvar id is 676492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132675353-G-A is described in CliVar as Benign. Clinvar id is 676492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLENM_006231.4 linkc.1226+45C>T intron_variant Intron 12 of 48 ENST00000320574.10 NP_006222.2 Q07864

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkc.1226+45C>T intron_variant Intron 12 of 48 1 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
AF:
0.0709
AC:
10793
AN:
152128
Hom.:
538
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.119
Gnomad AMI
AF:
0.0625
Gnomad AMR
AF:
0.135
Gnomad ASJ
AF:
0.0323
Gnomad EAS
AF:
0.000577
Gnomad SAS
AF:
0.0108
Gnomad FIN
AF:
0.0395
Gnomad MID
AF:
0.0601
Gnomad NFE
AF:
0.0445
Gnomad OTH
AF:
0.0597
GnomAD2 exomes
AF:
0.0609
AC:
14649
AN:
240560
AF XY:
0.0538
show subpopulations
Gnomad AFR exome
AF:
0.123
Gnomad AMR exome
AF:
0.177
Gnomad ASJ exome
AF:
0.0298
Gnomad EAS exome
AF:
0.000164
Gnomad FIN exome
AF:
0.0378
Gnomad NFE exome
AF:
0.0471
Gnomad OTH exome
AF:
0.0522
GnomAD4 exome
AF:
0.0473
AC:
68506
AN:
1447924
Hom.:
2322
Cov.:
31
AF XY:
0.0452
AC XY:
32532
AN XY:
719308
show subpopulations
African (AFR)
AF:
0.123
AC:
4096
AN:
33242
American (AMR)
AF:
0.173
AC:
7523
AN:
43500
Ashkenazi Jewish (ASJ)
AF:
0.0311
AC:
781
AN:
25076
East Asian (EAS)
AF:
0.000177
AC:
7
AN:
39562
South Asian (SAS)
AF:
0.0104
AC:
878
AN:
84404
European-Finnish (FIN)
AF:
0.0387
AC:
2005
AN:
51818
Middle Eastern (MID)
AF:
0.0486
AC:
276
AN:
5680
European-Non Finnish (NFE)
AF:
0.0453
AC:
50069
AN:
1104858
Other (OTH)
AF:
0.0480
AC:
2871
AN:
59784
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
2847
5695
8542
11390
14237
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
1970
3940
5910
7880
9850
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0711
AC:
10825
AN:
152246
Hom.:
547
Cov.:
32
AF XY:
0.0716
AC XY:
5327
AN XY:
74428
show subpopulations
African (AFR)
AF:
0.119
AC:
4933
AN:
41530
American (AMR)
AF:
0.136
AC:
2075
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.0323
AC:
112
AN:
3470
East Asian (EAS)
AF:
0.000579
AC:
3
AN:
5184
South Asian (SAS)
AF:
0.0114
AC:
55
AN:
4830
European-Finnish (FIN)
AF:
0.0395
AC:
419
AN:
10608
Middle Eastern (MID)
AF:
0.0646
AC:
19
AN:
294
European-Non Finnish (NFE)
AF:
0.0445
AC:
3027
AN:
68008
Other (OTH)
AF:
0.0591
AC:
125
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
502
1004
1506
2008
2510
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
112
224
336
448
560
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0522
Hom.:
166
Bravo
AF:
0.0801
Asia WGS
AF:
0.0180
AC:
63
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jun 14, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.92
CADD
Benign
0.045
DANN
Benign
0.49
PhyloP100
-1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs5744761; hg19: chr12-133251939; API