rs387907146
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024589.3(ROGDI):c.469C>T(p.Arg157Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 1,574,308 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
Consequence
NM_024589.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ROGDI | NM_024589.3 | c.469C>T | p.Arg157Ter | stop_gained | 7/11 | ENST00000322048.12 | |
ROGDI | XM_006720947.5 | c.469C>T | p.Arg157Ter | stop_gained | 7/11 | ||
ROGDI | XM_047434636.1 | c.199C>T | p.Arg67Ter | stop_gained | 5/9 | ||
ROGDI | NR_046480.2 | n.476C>T | non_coding_transcript_exon_variant | 6/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ROGDI | ENST00000322048.12 | c.469C>T | p.Arg157Ter | stop_gained | 7/11 | 1 | NM_024589.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000211 AC: 3AN: 1422148Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1AN XY: 704148
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
Amelocerebrohypohidrotic syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained p.R157* in ROGDI (NM_024589.3) has been reported previously in affected in patients from Israel (Mory A et al, 2012). The variant has been submitted to ClinVar as Pathogenic based on the same publication. The nonsense mutation would truncate a highly conserved C-terminal domain and functional study suggest deleterious effecte (Morya A et al,2012). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. The p.R157* variant is a loss of function variant in the gene ROGDI gene. There are 5 downstream pathogenic loss of function variants, with the furthest variant being 82 residues downstream of the variant p.R157*. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 06, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2022 | Variant summary: ROGDI c.469C>T (p.Arg157X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 190756 control chromosomes. c.469C>T has been reported in the literature as a homozygous genotype in multiple consanguineous individuals from a Druze village in Northern Israel affected with Amelocerebrohypohidrotic Syndrome (also referred to as KohlschutterTonz Syndrome) (example, Mory_2012 subsequently cited by others). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 31229). This premature translational stop signal has been observed in individuals with Kohlschutter syndrome (PMID: 22482807, 24630287). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg157*) in the ROGDI gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ROGDI are known to be pathogenic (PMID: 22424600, 23086778). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at