rs267608674
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_007055.4(POLR3A):c.2830G>T(p.Glu944*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,461,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
POLR3A
NM_007055.4 stop_gained
NM_007055.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.80
Genes affected
POLR3A (HGNC:30074): (RNA polymerase III subunit A) The protein encoded by this gene is the catalytic component of RNA polymerase III, which synthesizes small RNAs. The encoded protein also acts as a sensor to detect foreign DNA and trigger an innate immune response. [provided by RefSeq, Aug 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-77991125-C-A is Pathogenic according to our data. Variant chr10-77991125-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 41245.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-77991125-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLR3A | NM_007055.4 | c.2830G>T | p.Glu944* | stop_gained | 21/31 | ENST00000372371.8 | NP_008986.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLR3A | ENST00000372371.8 | c.2830G>T | p.Glu944* | stop_gained | 21/31 | 1 | NM_007055.4 | ENSP00000361446.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251158Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135734
GnomAD3 exomes
AF:
AC:
1
AN:
251158
Hom.:
AF XY:
AC XY:
0
AN XY:
135734
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461530Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727090
GnomAD4 exome
AF:
AC:
6
AN:
1461530
Hom.:
Cov.:
30
AF XY:
AC XY:
3
AN XY:
727090
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Leukodystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.Glu944Ter variant in POLR3A has been reported in 1 individual with hypomyelinating leukodystrophy (PMID: 21855841), and has been identified in 0.001% (1/113478) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608674). 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 (Variation ID#: 41245) and has been interpreted as pathogenic by GeneReviews. In vitro functional studies provide some evidence that the p.Glu944Ter variant may impact protein function (PMID: 21855841). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 944, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3A gene is an established disease mechanism in autosomal recessive hypomyelinating leukodystrophy. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PS3_moderate (Richards 2015). - |
Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at