chr12-132661166-T-G

Variant names:

• chr12-132661166-T-G
• rs867360056
• NM_006231.4:c.2865-2A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_006231.4(POLE):​c.2865-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000509 in 1,376,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLE NM_006231.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.9, offset of -43, new splice context is: cacagctggtggctccccAGcgc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.2865-2A>C		splice_acceptor_variant, intron_variant	Intron 24 of 48	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.2865-2A>C		splice_acceptor_variant, intron_variant	Intron 24 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 142298 Hom.: 0 Cov.: 32

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: 0.00000509 AC: 7 AN: 1376452 Hom.: 0 Cov.: 30 AF XY: 0.00000588 AC XY: 4 AN XY: 680548

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

African (AFR) AF: 0.0000336 AC: 1 AN: 29798

American (AMR) AF: 0.00 AC: 0 AN: 32004

Ashkenazi Jewish (ASJ) AF: 0.0000437 AC: 1 AN: 22886

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38100

South Asian (SAS) AF: 0.00 AC: 0 AN: 74210

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 46950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5062

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1070976

Other (OTH) AF: 0.0000177 AC: 1 AN: 56466

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 142362 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 68878

African (AFR) AF: 0.00 AC: 0 AN: 38460

American (AMR) AF: 0.00 AC: 0 AN: 13760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.00 AC: 0 AN: 4914

South Asian (SAS) AF: 0.00 AC: 0 AN: 4526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65378

Other (OTH) AF: 0.00 AC: 0 AN: 1958

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.0
GERP RS		5.3
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.87		Position offset: -22
DS_AL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs867360056; hg19: chr12-133237752;