rs5744761

chr12-132675353-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006231.4(POLE):c.1226+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,600,170 control chromosomes in the GnomAD database, including 2,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.071 (547 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2322 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.30

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-132675353-G-A is Benign according to our data. Variant chr12-132675353-G-A is described in ClinVar as [Benign]. Clinvar id is 676492.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-132675353-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.1226+45C>T		intron_variant		ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.1226+45C>T		intron_variant		1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.0709 AC: 10793 AN: 152128 Hom.: 538 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0445

Gnomad OTH AF: 0.0597

GnomAD3 exomes AF: 0.0609 AC: 14649 AN: 240560 Hom.: 817 AF XY: 0.0538 AC XY: 6993 AN XY: 129870

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00953

Gnomad FIN exome AF: 0.0378

Gnomad NFE exome AF: 0.0471

Gnomad OTH exome AF: 0.0522

GnomAD4 exome AF: 0.0473 AC: 68506 AN: 1447924 Hom.: 2322 Cov.: 31 AF XY: 0.0452 AC XY: 32532 AN XY: 719308

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.173

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.0387

Gnomad4 NFE exome AF: 0.0453

Gnomad4 OTH exome AF: 0.0480

GnomAD4 genome AF: 0.0711 AC: 10825 AN: 152246 Hom.: 547 Cov.: 32 AF XY: 0.0716 AC XY: 5327 AN XY: 74428

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0395

Gnomad4 NFE AF: 0.0445

Gnomad4 OTH AF: 0.0591

Alfa AF: 0.0523 Hom.: 150

Bravo AF: 0.0801

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.045
Dann	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs5744761; hg19: chr12-133251939;