10-78009519-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_007055.4(POLR3A):c.1909+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_007055.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152218Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome Pathogenic:2Other:1
This intronic variant (c.1909+18G>A) has not been observed in population databases (gnomAD), but several cases have been reported in the literature (PMID 21855841, PMID 27612211, PMID 30323018, PMID 12605447). Functional studies have not been published, although RNA analysis indicated altered splicing and retention of intronic nucletotides, leading to a shift in reading frame. In our laboratory, it was found homozygous in two affected siblings and heterozygous in each of their parents (with consanguinity reported). -
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not provided Pathogenic:2
This sequence change falls in intron 14 of the POLR3A gene. It does not directly change the encoded amino acid sequence of the POLR3A protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with leukodystrophy with oligodontia and/or Wiedemann–Rautenstrauch syndrome (PMID: 21855841, 27612211). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.2003+18G>A and c.1911+18C>T. ClinVar contains an entry for this variant (Variation ID: 31144). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
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Neonatal pseudo-hydrocephalic progeroid syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at