rs1555225324

chr12-132657941-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006231.4(POLE):c.3305A>C(p.Glu1102Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1102D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.3305A>C	p.Glu1102Ala	missense_variant	27/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.3305A>C	p.Glu1102Ala	missense_variant	27/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 14, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a POLE-related disease. This sequence change replaces glutamic acid with alanine at codon 1102 of the POLE protein (p.Glu1102Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.0065	T
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.41
Sift	Benign	0.032	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.97	D;D
Vest4		0.79
MutPred		0.56		Gain of catalytic residue at R1106 (P = 0.001);.;
MVP		0.61
MPC		1.5
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.50
gMVP		0.74

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

Other links and lift over

dbSNP: rs1555225324; hg19: chr12-133234527;