NM_002936.6:c.469C>T
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_002936.6(RNASEH1):c.469C>T(p.Arg157*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,940 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002936.6 stop_gained
Scores
Clinical Significance
Conservation
Publications
- progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Leigh syndromeInheritance: AR Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152094Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251448 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461846Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727226 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152094Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74270 show subpopulations
ClinVar
Submissions by phenotype
not provided Pathogenic:1
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this premature translational stop signal alters RNASEH1 gene expression (PMID: 26094573). ClinVar contains an entry for this variant (Variation ID: 372198). This premature translational stop signal has been observed in individual(s) with progressive external ophthalmoplegia with mitochondrial DNA deletions (PMID: 26094573, 28508084). 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 (rs373442996, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg157*) in the RNASEH1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RNASEH1 cause disease. -
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at