19-40397250-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_181882.3(PRX):c.1102C>T(p.Arg368*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000223 in 1,613,792 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 (★★).
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.1102C>T | p.Arg368* | stop_gained | Exon 7 of 7 | ENST00000324001.8 | NP_870998.2 | |
PRX | NM_001411127.1 | c.1387C>T | p.Arg463* | stop_gained | Exon 7 of 7 | NP_001398056.1 | ||
PRX | XM_017027047.2 | c.1000C>T | p.Arg334* | stop_gained | Exon 4 of 4 | XP_016882536.1 | ||
PRX | NM_020956.2 | c.*1307C>T | 3_prime_UTR_variant | Exon 6 of 6 | NP_066007.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249358Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135354
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461484Hom.: 0 Cov.: 35 AF XY: 0.0000261 AC XY: 19AN XY: 727064
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152308Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74482
ClinVar
Submissions by phenotype
not provided Pathogenic:2
The R368X nonsense variant in the PRX gene has been reported previously in an individual with Dejerine-Sottas neuropathy who had a second variant identified on the opposite PRX allele (in trans) (Boerkoel et al., 2001). This pathogenic variant is predicted to cause loss of normal protein function through protein truncation as the last 1094 amino acids of the protein are lost. The R368X variant is not observed in large population cohorts (Lek et al., 2016). -
PM2, PM3, PS4_moderate, PVS1_strong -
Charcot-Marie-Tooth disease type 4 Pathogenic:1Uncertain:1
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This sequence change creates a premature translational stop signal (p.Arg368*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1094 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 Dejerine-Sottas syndrome (PMID: 11133365). ClinVar contains an entry for this variant (Variation ID: 4789). This variant disrupts a region of the PRX protein in which other variant(s) (p.Arg1070*) have been determined to be pathogenic (PMID: 15197604, 16770524, 22847150, 26059842). 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. -
Inborn genetic diseases Pathogenic:1
The p.R368* variant (also known as c.1102C>T), located in coding exon 4 of the PRX gene, results from a C to T substitution at nucleotide position 1102. This changes the amino acid from an arginine to a stop codon within coding exon 4. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of PRX, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1,094 amino acids of the protein, which accounts for approximately 75% of the protein including the acidic domain. Additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing. This alteration has been reported in trans with another PRX variant in a patient with Dejerine-Sottas syndrome (Boerkoel CF et al. Am. J. Hum. Genet., 2001 Feb;68:325-33). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Peripheral neuropathy Pathogenic:1
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Charcot-Marie-Tooth disease type 4F Pathogenic:1
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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