rs4883544

Positions:

• chr12-132625361-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-132625361-T-C is Benign according to our data. Variant chr12-132625361-T-C is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.6657+284A>G		intron_variant		ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6716A>G	p.His2239Arg	missense_variant	48/48		XP_011533097.1
POLE	XM_011534797.4	c.5795A>G	p.His1932Arg	missense_variant	40/40		XP_011533099.1
POLE	XM_011534802.4	c.3704A>G	p.His1235Arg	missense_variant	24/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6657+284A>G		intron_variant		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

GnomAD3 exomes AF: 0.650 AC: 147125 AN: 226246 Hom.: 48952 AF XY: 0.637 AC XY: 79695 AN XY: 125106

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 SAS exome AF: 0.623

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

Gnomad4 AFR exome AF: 0.800

Gnomad4 AMR exome AF: 0.787

Gnomad4 ASJ exome AF: 0.530

Gnomad4 EAS exome AF: 0.806

Gnomad4 SAS exome AF: 0.618

Gnomad4 FIN exome AF: 0.572

Gnomad4 NFE exome AF: 0.586

Gnomad4 OTH exome AF: 0.622

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

Gnomad4 AFR AF: 0.808

Gnomad4 AMR AF: 0.740

Gnomad4 ASJ AF: 0.525

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.635

Gnomad4 FIN AF: 0.580

Gnomad4 NFE AF: 0.589

Gnomad4 OTH AF: 0.649

Alfa AF: 0.600 Hom.: 27829

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.053
DANN	Benign	0.066

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

Publications

LitVar

Other links and lift over

dbSNP: rs4883544; hg19: chr12-133201947; COSMIC: COSV57677025; COSMIC: COSV57677025;