rs797045102
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_181882.3(PRX):c.2289delT(p.Asp765ThrfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_181882.3 frameshift
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.2289delT | p.Asp765ThrfsTer10 | frameshift_variant | Exon 7 of 7 | ENST00000324001.8 | NP_870998.2 | |
PRX | NM_001411127.1 | c.2574delT | p.Asp860ThrfsTer10 | frameshift_variant | Exon 7 of 7 | NP_001398056.1 | ||
PRX | XM_017027047.2 | c.2187delT | p.Asp731ThrfsTer10 | frameshift_variant | Exon 4 of 4 | XP_016882536.1 | ||
PRX | NM_020956.2 | c.*2494delT | 3_prime_UTR_variant | Exon 6 of 6 | NP_066007.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461820Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1AN XY: 727210
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 4F Pathogenic:1
The Asp765ThrfsX10 variant in PRX has been reported in one compound heterozygous individual with peripheral neuropathy (Boerkoel 2011). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 765 and leads to a premature termination codon 10 amino acids downstream. This premature termination codon occurs in the last exon and therefore may escape nonsense mediated decay (NMD), resulting in a truncated protein. Importantly, several other truncating variants have been identified downstream of this position in several individuals with Charcot-Marie-Tooth disease type 4F (Boerkoel 2011, Kijima 2004, Marchesi 2010, Sivera 2013) indicating truncating variants in the last exon of PRX are not tolerated. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance (http://pcpgm.partners.org/LMM). -
Charcot-Marie-Tooth disease type 4 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asp765Thrfs*10) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 697 amino acid(s) of the PRX protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with PRX-related conditions (PMID: 11133365). This variant is also known as V763fsX774. ClinVar contains an entry for this variant (Variation ID: 208606). This variant disrupts a region of the PRX protein in which other variant(s) (p.Gln1169*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Autosomal recessive Dejerine-Sottas syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at