rs5744971
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The ENST00000320574.10(POLE):c.5570A>T(p.Lys1857Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K1857E) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000320574.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5570A>T | p.Lys1857Met | missense_variant | 41/49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.5570A>T | p.Lys1857Met | missense_variant | 41/48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.4649A>T | p.Lys1550Met | missense_variant | 33/40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.2558A>T | p.Lys853Met | missense_variant | 17/24 | XP_011533104.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.5570A>T | p.Lys1857Met | missense_variant | 41/49 | 1 | NM_006231.4 | ENSP00000322570 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151986Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251314Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135836
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461698Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727158
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151986Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74220
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 02, 2023 | This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1857 of the POLE protein (p.Lys1857Met). This variant is present in population databases (rs5744971, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 473744). 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 with a negative predictive value of 80%. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at