12-132624162-T-C

Variant names:

• chr12-132624162-T-C
• rs14302
• NM_006231.4:c.*535A>G

Variant summary

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

The NM_006231.4(POLE):​c.*535A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 216,668 control chromosomes in the GnomAD database, including 48,033 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 0.67 (35086 hom., cov: 32)
  • Exomes 𝑓: 0.62 (12947 hom.)
• Consequence: POLE NM_006231.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 17 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 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.*535A>G		3_prime_UTR	Exon 49 of 49	NP_006222.2	Q07864

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	ENST00000320574.10	TSL:1 MANE Select	c.*535A>G		3_prime_UTR	Exon 49 of 49	ENSP00000322570.5	Q07864
	POLE	ENST00000937600.1		c.*535A>G		3_prime_UTR	Exon 48 of 48	ENSP00000607659.1
	POLE	ENST00000541627.2	TSL:2	n.1696A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101923 AN: 151854 Hom.: 35053 Cov.: 32

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.646

GnomAD4 exome AF: 0.622 AC: 40263 AN: 64696 Hom.: 12947 Cov.: 0 AF XY: 0.621 AC XY: 18740 AN XY: 30164

African (AFR) AF: 0.801 AC: 2109 AN: 2632

American (AMR) AF: 0.733 AC: 1981 AN: 2702

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 2001 AN: 3844

East Asian (EAS) AF: 0.801 AC: 7331 AN: 9158

South Asian (SAS) AF: 0.556 AC: 439 AN: 790

European-Finnish (FIN) AF: 0.510 AC: 49 AN: 96

Middle Eastern (MID) AF: 0.595 AC: 226 AN: 380

European-Non Finnish (NFE) AF: 0.575 AC: 22978 AN: 39940

Other (OTH) AF: 0.611 AC: 3149 AN: 5154

GnomAD4 genome AF: 0.671 AC: 102009 AN: 151972 Hom.: 35086 Cov.: 32 AF XY: 0.673 AC XY: 49957 AN XY: 74274

African (AFR) AF: 0.808 AC: 33520 AN: 41496

American (AMR) AF: 0.740 AC: 11300 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1820 AN: 3462

East Asian (EAS) AF: 0.804 AC: 4114 AN: 5118

South Asian (SAS) AF: 0.636 AC: 3065 AN: 4822

European-Finnish (FIN) AF: 0.580 AC: 6130 AN: 10570

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39964 AN: 67910

Other (OTH) AF: 0.649 AC: 1372 AN: 2114

Alfa AF: 0.620 Hom.: 76190

Bravo AF: 0.688

Asia WGS AF: 0.706 AC: 2453 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.57
DANN	Benign	0.53
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs14302; hg19: chr12-133200748;