rs777454763

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006231.4(POLE):​c.2888G>T​(p.Gly963Val) 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

POLE
NM_006231.4 missense

Scores

12
4
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.85
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkuse as main transcriptc.2888G>T p.Gly963Val missense_variant 25/49 ENST00000320574.10 NP_006222.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.2888G>T p.Gly963Val missense_variant 25/491 NM_006231.4 ENSP00000322570 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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 25, 2022Algorithms 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. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 963 of the POLE protein (p.Gly963Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLE-related conditions. 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
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.43
T;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Benign
-0.36
T
MutationAssessor
Pathogenic
3.3
M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-7.7
D;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;D
Vest4
0.94
MutPred
0.54
Gain of catalytic residue at D962 (P = 8e-04);.;
MVP
0.67
MPC
1.8
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
3.8
Varity_R
0.90
gMVP
0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-133237727; API