chr12-132634254-T-C

Position:

• chr12-132634254-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006231.4(POLE):​c.5936A>G​(p.Asn1979Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. N1979T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.537

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15106481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.5936A>G	p.Asn1979Ser	missense_variant	43/49	ENST00000320574.10
POLE	XM_011534795.4	c.5936A>G	p.Asn1979Ser	missense_variant	43/48
POLE	XM_011534797.4	c.5015A>G	p.Asn1672Ser	missense_variant	35/40
POLE	XM_011534802.4	c.2924A>G	p.Asn975Ser	missense_variant	19/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.5936A>G	p.Asn1979Ser	missense_variant	43/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 15, 2018

This sequence change replaces asparagine with serine at codon 1979 of the POLE protein (p.Asn1979Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	D;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.12
Sift	Benign	0.21	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0	B;.
Vest4		0.073
MutPred		0.53		Gain of catalytic residue at N1978 (P = 0.079);.;
MVP		0.42
MPC		0.15
ClinPred		0.32	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.24

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: rs775893052; hg19: chr12-133210840;