12-132674148-C-G

Variant names:

• chr12-132674148-C-G
• rs5744769
• NM_006231.4:c.1227-441G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006231.4(POLE):​c.1227-441G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0976 in 151,738 control chromosomes in the GnomAD database, including 911 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.098 (911 hom., cov: 32)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.1227-441G>C		intron_variant	Intron 12 of 48	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.1227-441G>C		intron_variant	Intron 12 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.0977 AC: 14812 AN: 151620 Hom.: 911 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.00816

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.117

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0976 AC: 14810 AN: 151738 Hom.: 911 Cov.: 32 AF XY: 0.0936 AC XY: 6942 AN XY: 74156

African (AFR) AF: 0.0482 AC: 1991 AN: 41320

American (AMR) AF: 0.110 AC: 1677 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 520 AN: 3460

East Asian (EAS) AF: 0.00838 AC: 43 AN: 5134

South Asian (SAS) AF: 0.158 AC: 756 AN: 4786

European-Finnish (FIN) AF: 0.0340 AC: 359 AN: 10560

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.134 AC: 9095 AN: 67938

Other (OTH) AF: 0.118 AC: 247 AN: 2102

Alfa AF: 0.0457 Hom.: 51

Bravo AF: 0.0992

Asia WGS AF: 0.0880 AC: 307 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.77
DANN	Benign	0.41
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5744769; hg19: chr12-133250734;