rs4883544

Variant names:

• chr12-132625361-T-C
• rs4883544
• NM_006231.4:c.6657+284A>G

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.6657+284A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 729,596 control chromosomes in the GnomAD database, including 149,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35134 hom., cov: 34)
  • Exomes 𝑓: 0.62 (114142 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.22
• Publications: 23 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 (REVEL=0.0).
• BP6: Variant 12-132625361-T-C is Benign according to our data. Variant chr12-132625361-T-C is described in ClinVar as Benign. ClinVar VariationId is 1293826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.6657+284A>G		intron_variant	Intron 47 of 48	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6716A>G	p.His2239Arg	missense_variant	Exon 48 of 48		XP_011533097.1
POLE	XM_011534797.4	c.5795A>G	p.His1932Arg	missense_variant	Exon 40 of 40		XP_011533099.1
POLE	XM_011534802.4	c.3704A>G	p.His1235Arg	missense_variant	Exon 24 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6657+284A>G		intron_variant	Intron 47 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.671 AC: 102057 AN: 152048 Hom.: 35101 Cov.: 34

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.525

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.650 AC: 147125 AN: 226246 AF XY: 0.637

Gnomad AFR exome AF: 0.807

Gnomad AMR exome AF: 0.796

Gnomad ASJ exome AF: 0.530

Gnomad EAS exome AF: 0.815

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.583

Gnomad OTH exome AF: 0.630

GnomAD4 exome AF: 0.623 AC: 359607 AN: 577430 Hom.: 114142 Cov.: 3 AF XY: 0.618 AC XY: 195254 AN XY: 315974

African (AFR) AF: 0.800 AC: 13638 AN: 17040

American (AMR) AF: 0.787 AC: 33355 AN: 42358

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 10584 AN: 19952

East Asian (EAS) AF: 0.806 AC: 26676 AN: 33086

South Asian (SAS) AF: 0.618 AC: 42253 AN: 68354

European-Finnish (FIN) AF: 0.572 AC: 19570 AN: 34194

Middle Eastern (MID) AF: 0.621 AC: 2478 AN: 3990

European-Non Finnish (NFE) AF: 0.586 AC: 191799 AN: 327504

Other (OTH) AF: 0.622 AC: 19254 AN: 30952

GnomAD4 genome AF: 0.671 AC: 102143 AN: 152166 Hom.: 35134 Cov.: 34 AF XY: 0.673 AC XY: 50039 AN XY: 74396

African (AFR) AF: 0.808 AC: 33549 AN: 41530

American (AMR) AF: 0.740 AC: 11316 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 1822 AN: 3470

East Asian (EAS) AF: 0.805 AC: 4144 AN: 5150

South Asian (SAS) AF: 0.635 AC: 3071 AN: 4834

European-Finnish (FIN) AF: 0.580 AC: 6144 AN: 10600

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

European-Non Finnish (NFE) AF: 0.589 AC: 40003 AN: 67972

Other (OTH) AF: 0.649 AC: 1373 AN: 2114

Alfa AF: 0.613 Hom.: 37767

Bravo AF: 0.688

Asia WGS AF: 0.706 AC: 2454 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

- -

Jul 09, 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	-0.94
CADD	Benign	0.053
DANN	Benign	0.066
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4883544; hg19: chr12-133201947; COSMIC: COSV57677025; COSMIC: COSV57677025;