Genetic Variant NM_006231.4:c.2865-5_2865-4dupTT (chr12-132661167-G-GAA) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_006231.4(POLE):c.2865-5_2865-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,368,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00098 ( 0 hom. )

Consequence

POLE
NM_006231.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.191

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant 12-132661167-G-GAA is Benign according to our data. Variant chr12-132661167-G-GAA is described in ClinVar as [Likely_benign]. Clinvar id is 801260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000985 (1215/1233756) while in subpopulation SAS AF= 0.0027 (185/68468). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4_exome. There are 638 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.2865-5_2865-4dupTT		splice_region_variant, intron_variant	Intron 24 of 48	ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.2865-4_2865-3insTT		splice_region_variant, intron_variant	Intron 24 of 48	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.000156

AC:

AN:

134284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000129

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000178

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000985

AC:

1215

AN:

1233756

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

638

AN XY:

612260

show subpopulations

Gnomad4 AFR exome

AF:

0.00159

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.00113

Gnomad4 SAS exome

AF:

0.00270

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.000783

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.000156

AC:

AN:

134284

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

64610

show subpopulations

Gnomad4 AFR

AF:

0.000249

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000129

Gnomad4 NFE

AF:

0.000178

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Mar 11, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over