rs138305578
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_007055.4(POLR3A):āc.3392A>Gā(p.Lys1131Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007055.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251058Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135698
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460516Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 726648
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74358
ClinVar
Submissions by phenotype
not provided Uncertain:2
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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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 549572). This missense change has been observed in individual(s) with Wiedemann-Rautenstrauch syndrome (PMID: 30323018). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs138305578, gnomAD 0.03%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1131 of the POLR3A protein (p.Lys1131Arg). -
Neonatal pseudo-hydrocephalic progeroid syndrome Pathogenic:1
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Leukodystrophy Uncertain:1
The p.Lys1131Arg variant in POLR3A has been reported in 2 individuals with POLR3A-related disorders (PMID: 30323018, Yananoto et al. 2017), and has been identified in 0.05% (13/24956) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs138305578). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This Lys1131Arg variant has also been reported in ClinVar (Variation ID#: 549572) and has been interpreted as likely pathogenic by the Tartaglia Lab (Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital) and as a variant of uncertain significance by Invitae. Of the 2 affected individuals, 1 was a compound heterozygote that carried a likely pathogenic variant in trans, which increases the likelihood that the p.Lys1131Arg variant is pathogenic (PMID: 30323018). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Lys1131Arg variant is located in a region of POLR3A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30323018). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3, PM1_supporting (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at