rs104894706
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_181882.3(PRX):c.586C>T(p.Arg196*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,566,998 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 (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PRX
NM_181882.3 stop_gained
NM_181882.3 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 0.340
Genes affected
PRX (HGNC:13797): (periaxin) This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-40397766-G-A is Pathogenic according to our data. Variant chr19-40397766-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40397766-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.586C>T | p.Arg196* | stop_gained | 7/7 | ENST00000324001.8 | NP_870998.2 | |
PRX | NM_001411127.1 | c.871C>T | p.Arg291* | stop_gained | 7/7 | NP_001398056.1 | ||
PRX | XM_017027047.2 | c.484C>T | p.Arg162* | stop_gained | 4/4 | XP_016882536.1 | ||
PRX | NM_020956.2 | c.*791C>T | 3_prime_UTR_variant | 6/6 | NP_066007.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRX | ENST00000324001.8 | c.586C>T | p.Arg196* | stop_gained | 7/7 | 1 | NM_181882.3 | ENSP00000326018.6 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000141 AC: 2AN: 1414802Hom.: 0 Cov.: 35 AF XY: 0.00000143 AC XY: 1AN XY: 699472
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74358
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 20, 2020 | - - |
Charcot-Marie-Tooth disease type 4F Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 15, 2001 | - - |
Charcot-Marie-Tooth disease type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 01, 2020 | This variant has been observed to be homozygous or in combination with another PRX variant in individuals and a large family affected with Charcot-Marie-Tooth disease (PMID: 24011642, 11157804). ClinVar contains an entry for this variant (Variation ID: 4791). For these reasons, this variant has been classified as Pathogenic. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change results in a premature translational stop signal in the PRX gene (p.Arg196*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1,266 amino acids of the PRX protein. - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at