rs772127913

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006231.4(POLE):c.5912A>G(p.Asn1971Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,090 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1971K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 0.932

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026675552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLE	NM_006231.4 linkuse as main transcript	c.5912A>G	p.Asn1971Ser	missense_variant	43/49	ENST00000320574.10
POLE	XM_011534795.4 linkuse as main transcript	c.5912A>G	p.Asn1971Ser	missense_variant	43/48
POLE	XM_011534797.4 linkuse as main transcript	c.4991A>G	p.Asn1664Ser	missense_variant	35/40
POLE	XM_011534802.4 linkuse as main transcript	c.2900A>G	p.Asn967Ser	missense_variant	19/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.5912A>G	p.Asn1971Ser	missense_variant	43/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

248984

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2018	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in the compound heterozygous state with POLE p.Glu1956Val in an individual reportedly presenting with a FILS-like (facial dysmorphism, immunodeficiency, livedo, and short stature) phenotype (Mestek-Boukhibar 2018). While POLE c.4444+3A>G, a leaky splice variant, has been reported as homozygous in individuals with FILS (Pachlopnik Schmid 2012, Thiffault 2015), it is not clear whether biallelic POLE missense variants result in a similar phenotype.; This variant is associated with the following publications: (PMID: 30049826) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 21, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLE protein function. ClinVar contains an entry for this variant (Variation ID: 439278). This missense change has been observed in individual(s) with FILS (facial dysmorphism, immunodeficiency, livedo, and short stature) syndrome (PMID: 30049826). This variant is present in population databases (rs772127913, gnomAD 0.02%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1971 of the POLE protein (p.Asn1971Ser). -

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Translational Omics - GOSgene, University College London

Mar 16, 2018

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.73

Cadd

Benign

0.59

Dann

Benign

0.23

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.34

N;N

REVEL

Benign

0.018

Sift

Benign

0.47

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.0020

B;.

Vest4

0.030

MVP

0.18

MPC

0.15

ClinPred

0.0075

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.13

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over