19-40396791-GTACCTCTGGAAGCCGCACCTCCGGCACAGCCATCTCTGGCACCTTTGGGAGTTTCATCTCTGACACTTTGGGCAGCTC-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_181882.3(PRX):βc.1483_1560delβ(p.Glu495_Val520del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 142,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000042 ( 0 hom., cov: 32)
Consequence
PRX
NM_181882.3 inframe_deletion
NM_181882.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.15
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_181882.3.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.1483_1560del | p.Glu495_Val520del | inframe_deletion | 7/7 | ENST00000324001.8 | |
PRX | NM_001411127.1 | c.1768_1845del | p.Glu590_Val615del | inframe_deletion | 7/7 | ||
PRX | XM_017027047.2 | c.1381_1458del | p.Glu461_Val486del | inframe_deletion | 4/4 | ||
PRX | NM_020956.2 | c.*1688_*1765del | 3_prime_UTR_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRX | ENST00000324001.8 | c.1483_1560del | p.Glu495_Val520del | inframe_deletion | 7/7 | 1 | NM_181882.3 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000422 AC: 6AN: 142240Hom.: 0 Cov.: 32
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GnomAD4 genome AF: 0.0000422 AC: 6AN: 142240Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 4AN XY: 69172
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 25, 2021 | The c.1483_1560del78 variant (also known as p.E495_V520del) is located in coding exon 4 of the PRX gene. This variant results from an in-frame deletion of 78 nucleotides at nucleotide positions 1483 to 1560. This results in the deletion of 26 amino acids between codons 495 and 520. This amino acid region is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 4F Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Apr 27, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2018 | A variant of uncertain significance has been identified in the PRX gene. The c.1483_1560del78 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1483_1560del78 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1483_1560del78 variant results in an in-frame deletion of 26 amino acids, denoted p.Glu495_Val520del. In-frame deletions of the PRX gene have not been previously reported in association with neuropathy to our knowledge (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 410606). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.1483_1560del, results in the deletion of 26 amino acid(s) of the PRX protein (p.Glu495_Val520del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at