rs181087667
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_007055.4(POLR3A):c.2617-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_007055.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLR3A | NM_007055.4 | c.2617-1G>A | splice_acceptor_variant | ENST00000372371.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLR3A | ENST00000372371.8 | c.2617-1G>A | splice_acceptor_variant | 1 | NM_007055.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251114Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135724
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1460962Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19AN XY: 726890
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74426
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change affects an acceptor splice site in intron 19 of the POLR3A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POLR3A are known to be pathogenic (PMID: 21855841, 25339210, 27612211, 30414627, 30450527). This variant is present in population databases (rs181087667, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with POLR3A-related conditions (PMID: 21855841). This variant is also known as c.2711-1G>A. ClinVar contains an entry for this variant (Variation ID: 31146). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25339210, 21855841, 30414627, 30323018, 28459997) - |
Neonatal pseudo-hydrocephalic progeroid syndrome Pathogenic:4
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 09, 2011 | - - |
Likely pathogenic, criteria provided, single submitter | research | Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital | May 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | research | Cole/Wambach Lab, Washington University in St. Louis | Oct 01, 2018 | - - |
Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 09, 2011 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Leukodystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The c.2617-1G>A variant in POLR3A has been reported in 5 individuals with POLR3A-related disorders (PMID: 28459997, 30323018, 30414627, 25339210, 21855841), and has been identified in (7/128958) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs181087667). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 31146) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. Of the 5 affected individuals, at least 1 was a compound heterozygote that carried a reported pathogenic variants in trans, which increases the likelihood that the c.2617-1G>A variant is pathogenic (VariationID: 445922, 31145; PMID: 28459997, 30323018). In vitro functional studies provide some evidence that the c.2617-1G>A variant may impact protein function (PMID: 21855841). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. SpliceAI predictions indicate use of an out-of-frame cryptic splice site 5 bases from the intron-exon boundary, providing evidence that this variant may cause a frameshift and lead to a premature termination codon downstream. This alteration is then predicted to lead to a truncated or absent protein. However, this information is not predictive enough to determine pathogenicity. Loss of function of the POLR3A gene is an established disease mechanism in autosomal recessive POLR3A-related disorders. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1_strong, PM3, PM2_supporting, PS3_moderate (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at