12-132650245-C-T

Variant names:

• chr12-132650245-C-T
• rs5744897
• NM_006231.4:c.3583-356G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.3583-356G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 268,702 control chromosomes in the GnomAD database, including 1,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (863 hom., cov: 32)
  • Exomes 𝑓: 0.095 (686 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.821
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 12-132650245-C-T is Benign according to our data. Variant chr12-132650245-C-T is described in ClinVar as Benign. ClinVar VariationId is 1238899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.3583-356G>A		intron_variant	Intron 29 of 48	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3583-356G>A		intron_variant	Intron 29 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15279 AN: 151946 Hom.: 856 Cov.: 32

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.0908

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.0319

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.108

GnomAD4 exome AF: 0.0950 AC: 11082 AN: 116638 Hom.: 686 Cov.: 0 AF XY: 0.0963 AC XY: 5781 AN XY: 60052

African (AFR) AF: 0.0790 AC: 325 AN: 4116

American (AMR) AF: 0.0733 AC: 374 AN: 5102

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 398 AN: 3562

East Asian (EAS) AF: 0.000287 AC: 2 AN: 6980

South Asian (SAS) AF: 0.120 AC: 1643 AN: 13744

European-Finnish (FIN) AF: 0.0367 AC: 204 AN: 5562

Middle Eastern (MID) AF: 0.0816 AC: 40 AN: 490

European-Non Finnish (NFE) AF: 0.106 AC: 7460 AN: 70390

Other (OTH) AF: 0.0950 AC: 636 AN: 6692

GnomAD4 genome AF: 0.101 AC: 15307 AN: 152064 Hom.: 863 Cov.: 32 AF XY: 0.0964 AC XY: 7165 AN XY: 74340

African (AFR) AF: 0.0960 AC: 3980 AN: 41458

American (AMR) AF: 0.0907 AC: 1385 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 405 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.138 AC: 667 AN: 4818

European-Finnish (FIN) AF: 0.0319 AC: 338 AN: 10586

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8199 AN: 67968

Other (OTH) AF: 0.107 AC: 225 AN: 2108

Alfa AF: 0.0841 Hom.: 316

Bravo AF: 0.104

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.15
DANN	Benign	0.80
PhyloP100		-0.82
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: rs5744897; hg19: chr12-133226831;