Genetic Variant POLE:c.2865-6_2865-4dupTTT (chr12-132661167-G-GAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006231.4(POLE):c.2865-6_2865-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000064 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POLE
NM_006231.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.191

Publications

0 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

POLE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.2865-6_2865-4dupTTT		splice_region intron	N/A	NP_006222.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
POLE	ENST00000320574.10	TSL:1 MANE Select	c.2865-4_2865-3insTTT	splice_region intron	N/A	ENSP00000322570.5
POLE	ENST00000535270.5	TSL:1	c.2784-4_2784-3insTTT	splice_region intron	N/A	ENSP00000445753.1
POLE	ENST00000537064.5	TSL:1	n.1912-4_1912-3insTTT	splice_region intron	N/A	ENSP00000442578.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

134300

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000635

AC:

AN:

1243544

Hom.:

Cov.:

AF XY:

0.0000616

AC XY:

AN XY:

617100

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000367

AC:

AN:

27244

American (AMR)

AF:

0.0000643

AC:

AN:

31104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21222

East Asian (EAS)

AF:

0.000110

AC:

AN:

36332

South Asian (SAS)

AF:

0.000303

AC:

AN:

69286

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

41358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4602

European-Non Finnish (NFE)

AF:

0.0000448

AC:

AN:

960626

Other (OTH)

AF:

0.0000773

AC:

AN:

51770

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

134300

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64614

African (AFR)

AF:

0.00

AC:

AN:

36128

American (AMR)

AF:

0.00

AC:

AN:

13540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3228

East Asian (EAS)

AF:

0.00

AC:

AN:

4652

South Asian (SAS)

AF:

0.00

AC:

AN:

4176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61914

Other (OTH)

AF:

0.00

AC:

AN:

1768

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

12-132661167-GAAAAA-GAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over