rs1060500809
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_006231.4(POLE):c.6088del(p.Ala2030ProfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2030A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006231.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6088del | p.Ala2030ProfsTer18 | frameshift_variant | 44/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6088del | p.Ala2030ProfsTer18 | frameshift_variant | 44/48 | ||
POLE | XM_011534797.4 | c.5167del | p.Ala1723ProfsTer18 | frameshift_variant | 36/40 | ||
POLE | XM_011534802.4 | c.3076del | p.Ala1026ProfsTer18 | frameshift_variant | 20/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6088del | p.Ala2030ProfsTer18 | frameshift_variant | 44/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461536Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727098
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 405682). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala2030Profs*18) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 07, 2019 | The c.6088delG variant, located in coding exon 44 of the POLE gene, results from a deletion of one nucleotide at nucleotide position 6088, causing a translational frameshift with a predicted alternate stop codon. As neither this specific alteration nor loss of function as a mechanism of pathogenicity have been well-described in the POLE gene, the clinical significance of this variant remains unknown (ACMG Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015 May;17(5):405-23). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at