rs104894714
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_181882.3(PRX):c.2857C>T(p.Arg953Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,894 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R953R) has been classified as Likely benign.
Frequency
Consequence
NM_181882.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.2857C>T | p.Arg953Ter | stop_gained | 7/7 | ENST00000324001.8 | |
PRX | NM_001411127.1 | c.3142C>T | p.Arg1048Ter | stop_gained | 7/7 | ||
PRX | XM_017027047.2 | c.2755C>T | p.Arg919Ter | stop_gained | 4/4 | ||
PRX | NM_020956.2 | c.*3062C>T | 3_prime_UTR_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRX | ENST00000324001.8 | c.2857C>T | p.Arg953Ter | stop_gained | 7/7 | 1 | NM_181882.3 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251340Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135862
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461894Hom.: 0 Cov.: 99 AF XY: 0.0000110 AC XY: 8AN XY: 727248
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 11, 2019 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2018 | The R953X variant in the PRX gene has been reported previously in the compound heterozygous state in an individual with Dejerine-Sottas Neuropathy (Boerkoel et al., 2001). This variant is predicted to cause loss of normal protein function through protein truncation, as the last 509 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014). The R953X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R953X as a pathogenic variant. - |
Charcot-Marie-Tooth disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease type 4F Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 14-year-old female with Charcot Marie Tooth disease. Heterozygotes are expected to be asymptomatic carriers. - |
Charcot-Marie-Tooth disease type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRX protein in which other variant(s) (p.R1070*) have been determined to be pathogenic (PMID: 15197604, 16770524, 22847150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 4787). This premature translational stop signal has been observed in individuals with Dejerine-Sottas syndrome (PMID: 11133365). This variant is present in population databases (rs104894714, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg953*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 509 amino acid(s) of the PRX protein. - |
Autosomal recessive Dejerine-Sottas syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2001 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at