12-132661167-GA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_006231.4(POLE):​c.2865-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 134,162 control chromosomes in the GnomAD database, including 209 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 209 hom., cov: 31)
Exomes 𝑓: 0.21 ( 106 hom. )
Failed GnomAD Quality Control

Consequence

POLE
NM_006231.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant 12-132661167-GA-G is Benign according to our data. Variant chr12-132661167-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 695292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132661167-GA-G is described in Lovd as [Benign]. Variant chr12-132661167-GA-G is described in Lovd as [Likely_benign]. Variant chr12-132661167-GA-G is described in Lovd as [Likely_benign]. Variant chr12-132661167-GA-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkuse as main transcriptc.2865-4delT splice_region_variant, intron_variant ENST00000320574.10 NP_006222.2 Q07864

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.2865-4delT splice_region_variant, intron_variant 1 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
AF:
0.0425
AC:
5696
AN:
134136
Hom.:
202
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0115
Gnomad AMI
AF:
0.0428
Gnomad AMR
AF:
0.133
Gnomad ASJ
AF:
0.0344
Gnomad EAS
AF:
0.00194
Gnomad SAS
AF:
0.0228
Gnomad FIN
AF:
0.0486
Gnomad MID
AF:
0.0272
Gnomad NFE
AF:
0.0450
Gnomad OTH
AF:
0.0334
GnomAD4 exome
Data not reliable, filtered out with message: InbreedingCoeff
AF:
0.213
AC:
212152
AN:
996606
Hom.:
106
Cov.:
0
AF XY:
0.215
AC XY:
106028
AN XY:
493402
show subpopulations
Gnomad4 AFR exome
AF:
0.187
Gnomad4 AMR exome
AF:
0.334
Gnomad4 ASJ exome
AF:
0.224
Gnomad4 EAS exome
AF:
0.208
Gnomad4 SAS exome
AF:
0.225
Gnomad4 FIN exome
AF:
0.234
Gnomad4 NFE exome
AF:
0.207
Gnomad4 OTH exome
AF:
0.216
GnomAD4 genome
AF:
0.0425
AC:
5708
AN:
134162
Hom.:
209
Cov.:
31
AF XY:
0.0447
AC XY:
2886
AN XY:
64570
show subpopulations
Gnomad4 AFR
AF:
0.0115
Gnomad4 AMR
AF:
0.134
Gnomad4 ASJ
AF:
0.0344
Gnomad4 EAS
AF:
0.00194
Gnomad4 SAS
AF:
0.0231
Gnomad4 FIN
AF:
0.0486
Gnomad4 NFE
AF:
0.0450
Gnomad4 OTH
AF:
0.0331
Bravo
AF:
0.0420

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not provided Benign:2
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 13, 2019- -
Colorectal cancer, susceptibility to, 12 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2019- -
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 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 17, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369732588; hg19: chr12-133237753; API