chr12-132643245-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006231.4(POLE):c.4530A>G(p.Ala1510Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,612,906 control chromosomes in the GnomAD database, including 178,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 23127 hom., cov: 34)

Exomes 𝑓: 0.46 ( 155809 hom. )

Consequence

POLE
NM_006231.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -2.77

Publications

30 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 12-132643245-T-C is Benign according to our data. Variant chr12-132643245-T-C is described in ClinVar as Benign. ClinVar VariationId is 380214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.77 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 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.4530A>G	p.Ala1510Ala	synonymous	Exon 35 of 49	NP_006222.2	Q07864

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLE	ENST00000320574.10	TSL:1 MANE Select	c.4530A>G	p.Ala1510Ala	synonymous	Exon 35 of 49	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.4449A>G	p.Ala1483Ala	synonymous	Exon 34 of 48	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.*4281A>G		non_coding_transcript_exon	Exon 35 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.535

AC:

81384

AN:

152068

Hom.:

23080

Cov.:

show subpopulations

Gnomad AFR

AF:

0.715

Gnomad AMI

AF:

0.323

Gnomad AMR

AF:

0.554

Gnomad ASJ

AF:

0.382

Gnomad EAS

AF:

0.701

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.433

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.528

GnomAD2 exomes

AF:

0.504

AC:

124284

AN:

246480

AF XY:

0.497

show subpopulations

Gnomad AFR exome

AF:

0.716

Gnomad AMR exome

AF:

0.578

Gnomad ASJ exome

AF:

0.389

Gnomad EAS exome

AF:

0.704

Gnomad FIN exome

AF:

0.430

Gnomad NFE exome

AF:

0.431

Gnomad OTH exome

AF:

0.474

GnomAD4 exome

AF:

0.456

AC:

666555

AN:

1460720

Hom.:

155809

Cov.:

AF XY:

0.458

AC XY:

333049

AN XY:

726654

show subpopulations

African (AFR)

AF:

0.716

AC:

23958

AN:

33468

American (AMR)

AF:

0.572

AC:

25565

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

10172

AN:

26130

East Asian (EAS)

AF:

0.697

AC:

27670

AN:

39692

South Asian (SAS)

AF:

0.546

AC:

47106

AN:

86240

European-Finnish (FIN)

AF:

0.427

AC:

22610

AN:

52930

Middle Eastern (MID)

AF:

0.511

AC:

2947

AN:

5768

European-Non Finnish (NFE)

AF:

0.430

AC:

478116

AN:

1111434

Other (OTH)

AF:

0.471

AC:

28411

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

19591

39182

58772

78363

97954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14808

29616

44424

59232

74040

<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:

0.535

AC:

81479

AN:

152186

Hom.:

23127

Cov.:

AF XY:

0.537

AC XY:

39975

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.715

AC:

29703

AN:

41520

American (AMR)

AF:

0.554

AC:

8476

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.382

AC:

1326

AN:

3472

East Asian (EAS)

AF:

0.701

AC:

3624

AN:

5170

South Asian (SAS)

AF:

0.558

AC:

2695

AN:

4826

European-Finnish (FIN)

AF:

0.433

AC:

4585

AN:

10596

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.434

AC:

29510

AN:

67996

Other (OTH)

AF:

0.530

AC:

1119

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1928

3855

5783

7710

9638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.463

Hom.:

59024

Bravo

AF:

0.551

Asia WGS

AF:

0.589

AC:

2046

AN:

3478

EpiCase

AF:

0.433

EpiControl

AF:

0.430

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 (1)

Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (1)

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

Hereditary cancer-predisposing 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

-0.75

CADD

Benign

0.020

(source)

DANN

Benign

0.34

PhyloP100

-2.8

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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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