rs753680242
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_006231.4(POLE):āc.5528A>Gā(p.Asn1843Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5528A>G | p.Asn1843Ser | missense_variant | 40/49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.5528A>G | p.Asn1843Ser | missense_variant | 40/48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.4607A>G | p.Asn1536Ser | missense_variant | 32/40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.2516A>G | p.Asn839Ser | missense_variant | 16/24 | XP_011533104.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.5528A>G | p.Asn1843Ser | missense_variant | 40/49 | 1 | NM_006231.4 | ENSP00000322570.5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251326Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135824
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727226
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74296
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 02, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1843 of the POLE protein (p.Asn1843Ser). This variant is present in population databases (rs753680242, gnomAD 0.009%). 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: 240564). 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. 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at