rs267608670
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_007055.4(POLR3A):c.2015G>A(p.Gly672Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_007055.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLR3A | NM_007055.4 | c.2015G>A | p.Gly672Glu | missense_variant | 15/31 | ENST00000372371.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLR3A | ENST00000372371.8 | c.2015G>A | p.Gly672Glu | missense_variant | 15/31 | 1 | NM_007055.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251470Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135906
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461730Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727176
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74474
ClinVar
Submissions by phenotype
Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2024 | The p.Gly672Glu variant in POLR3A has been reported in 7 individuals with POLR3A-related disorders (PMID: 21855841, 33005949, 25339210), and has been identified in 0.006% (1/16256) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608670). 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. Of the 7 affected individuals, 2 of those were homozygotes, which increases the likelihood that the p.Gly672Glu variant is pathogenic (PMID: 21855841, 33005949). This variant has also been reported in ClinVar (Variation ID#: 31143) and has been interpreted as pathogenic by GeneReviews and OMIM. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly672Glu variant is uncertain. ACMG/AMP Criteria applied: PM3, PM2_supporting, PP3 (Richards 2015). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 09, 2011 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
POLR3A-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 01, 2024 | The POLR3A c.2015G>A variant is predicted to result in the amino acid substitution p.Gly672Glu. This variant was reported both in the homozygous and compound heterozygous states in patients with hypomyelinating leukodystrophy (Bernard et al. 2011. PubMed ID: 21855841; Supplementary table e-1, Wolf et al. 2014. PubMed ID: 25339210). A recent study reviewed that this variant in the homozygous state did present typical neurological features of hypomyelinating leukodystrophy (4H leukodystrophy), although transgenic mouse models of this variant (in the homozygous state or in the compound heterozygous state with one null allele) did not demonstrate the phenotype of childhood-onset hypomyelinating leukodystrophy (Pelletier et al. 2021. PubMed ID: 33005949; Choquet et al. 2017. PubMed ID: 28407788). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Based on the given information, this variant is classified as likely pathogenic. - |
Pol III-related leukodystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 14, 2024 | Variant summary: POLR3A c.2015G>A (p.Gly672Glu) results in a non-conservative amino acid change located in the RNA polymerase Rpb1, domain 3 (IPR007066) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251470 control chromosomes (gnomAD). c.2015G>A has been reported in the literature in multiple individuals affected with Tremor-ataxia with central hypomyelinating leukodystrophy (e.g. Bernard_2011). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 21855841). ClinVar contains an entry for this variant (Variation ID: 31143). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at