rs5745075

Variant names:

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.6657+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,611,794 control chromosomes in the GnomAD database, including 91,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10024 hom., cov: 33)

Exomes 𝑓: 0.33 ( 81770 hom. )

Consequence

POLE
NM_006231.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.52

Publications

11 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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

POLE links:

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=-0.87).

BP6

Variant 12-132625629-G-A is Benign according to our data. Variant chr12-132625629-G-A is described in ClinVar as Benign. ClinVar VariationId is 371835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006231.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.6657+16C>T		intron	N/A	NP_006222.2	Q07864

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLE	ENST00000320574.10	TSL:1 MANE Select	c.6657+16C>T	intron	N/A	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.6576+16C>T	intron	N/A	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.*6408+16C>T	intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.353

AC:

53617

AN:

151992

Hom.:

10011

Cov.:

show subpopulations

Gnomad AFR

AF:

0.366

Gnomad AMI

AF:

0.262

Gnomad AMR

AF:

0.412

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.693

Gnomad SAS

AF:

0.374

Gnomad FIN

AF:

0.407

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.304

Gnomad OTH

AF:

0.342

GnomAD2 exomes

AF:

0.376

AC:

94000

AN:

249782

AF XY:

0.368

show subpopulations

Gnomad AFR exome

AF:

0.365

Gnomad AMR exome

AF:

0.489

Gnomad ASJ exome

AF:

0.233

Gnomad EAS exome

AF:

0.696

Gnomad FIN exome

AF:

0.401

Gnomad NFE exome

AF:

0.304

Gnomad OTH exome

AF:

0.334

GnomAD4 exome

AF:

0.325

AC:

475107

AN:

1459684

Hom.:

81770

Cov.:

AF XY:

0.327

AC XY:

237143

AN XY:

726222

show subpopulations

African (AFR)

AF:

0.360

AC:

12044

AN:

33470

American (AMR)

AF:

0.476

AC:

21283

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

6011

AN:

26106

East Asian (EAS)

AF:

0.693

AC:

27522

AN:

39698

South Asian (SAS)

AF:

0.372

AC:

32035

AN:

86224

European-Finnish (FIN)

AF:

0.391

AC:

20276

AN:

51816

Middle Eastern (MID)

AF:

0.339

AC:

1956

AN:

5766

European-Non Finnish (NFE)

AF:

0.301

AC:

334444

AN:

1111544

Other (OTH)

AF:

0.324

AC:

19536

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

16037

32073

48110

64146

80183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11290

22580

33870

45160

56450

<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:

0.353

AC:

53646

AN:

152110

Hom.:

10024

Cov.:

AF XY:

0.360

AC XY:

26786

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.365

AC:

15152

AN:

41510

American (AMR)

AF:

0.412

AC:

6301

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

778

AN:

3468

East Asian (EAS)

AF:

0.693

AC:

3579

AN:

5166

South Asian (SAS)

AF:

0.374

AC:

1797

AN:

4806

European-Finnish (FIN)

AF:

0.407

AC:

4306

AN:

10586

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.304

AC:

20671

AN:

67976

Other (OTH)

AF:

0.344

AC:

727

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1787

3574

5362

7149

8936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<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:

0.314

Hom.:

1438

Bravo

AF:

0.356

Asia WGS

AF:

0.469

AC:

1626

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Colorectal cancer, susceptibility to, 12 (2)

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (1)

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.15

(source)

DANN

Benign

0.47

PhyloP100

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over