12-132632665-G-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7
The NM_006231.4(POLE):c.6135C>A(p.Pro2045=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P2045P) has been classified as Likely benign.
Frequency
Consequence
NM_006231.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6135C>A | p.Pro2045= | splice_region_variant, synonymous_variant | 44/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6135C>A | p.Pro2045= | splice_region_variant, synonymous_variant | 44/48 | ||
POLE | XM_011534797.4 | c.5214C>A | p.Pro1738= | splice_region_variant, synonymous_variant | 36/40 | ||
POLE | XM_011534802.4 | c.3123C>A | p.Pro1041= | splice_region_variant, synonymous_variant | 20/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6135C>A | p.Pro2045= | splice_region_variant, synonymous_variant | 44/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250618Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135648
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461694Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727134
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2020 | This variant has not been reported in the literature in individuals with POLE-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 2045 of the POLE mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the POLE protein. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at