rs5744761

Variant names:

• chr12-132675353-G-A
• rs5744761
• NM_006231.4:c.1226+45C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-132675353-G-A
• chr12-132675353-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.30
• Publications: 9 publications found

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

ACMG classification

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
POLE	NM_006231.4	c.1226+45C>T		intron_variant	Intron 12 of 48	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.1226+45C>T		intron_variant	Intron 12 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.0709 AC: 10793 AN: 152128 Hom.: 538 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.0711 AC: 10825 AN: 152246 Hom.: 547 Cov.: 32 AF XY: 0.0716 AC XY: 5327 AN XY: 74428

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

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

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

Other links and lift over

dbSNP: rs5744761; hg19: chr12-133251939;