rs744389
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The ENST00000324001.8(PRX):c.306C>T(p.Thr102=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,946 control chromosomes in the GnomAD database, including 25,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.13 ( 1514 hom., cov: 32)
Exomes 𝑓: 0.17 ( 24019 hom. )
Consequence
PRX
ENST00000324001.8 synonymous
ENST00000324001.8 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.250
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 Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
Variant 19-40398695-G-A is Benign according to our data. Variant chr19-40398695-G-A is described in ClinVar as [Benign]. Clinvar id is 130051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40398695-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.25 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.306C>T | p.Thr102= | synonymous_variant | 6/7 | ENST00000324001.8 | NP_870998.2 | |
PRX | NM_001411127.1 | c.591C>T | p.Thr197= | synonymous_variant | 6/7 | NP_001398056.1 | ||
PRX | NM_020956.2 | c.306C>T | p.Thr102= | synonymous_variant | 6/6 | NP_066007.1 | ||
PRX | XM_017027047.2 | c.204C>T | p.Thr68= | synonymous_variant | 3/4 | XP_016882536.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRX | ENST00000324001.8 | c.306C>T | p.Thr102= | synonymous_variant | 6/7 | 1 | NM_181882.3 | ENSP00000326018 | A2 |
Frequencies
GnomAD3 genomes AF: 0.126 AC: 19172AN: 152106Hom.: 1515 Cov.: 32
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GnomAD3 exomes AF: 0.140 AC: 35121AN: 250146Hom.: 2951 AF XY: 0.148 AC XY: 20046AN XY: 135382
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GnomAD4 exome AF: 0.175 AC: 255736AN: 1461722Hom.: 24019 Cov.: 36 AF XY: 0.175 AC XY: 127596AN XY: 727186
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GnomAD4 genome AF: 0.126 AC: 19167AN: 152224Hom.: 1514 Cov.: 32 AF XY: 0.123 AC XY: 9147AN XY: 74424
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ClinVar
Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:6
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Charcot-Marie-Tooth disease type 4F Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 25, 2017 | - - |
Charcot-Marie-Tooth disease Benign:1
Benign, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
not provided Benign:1
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Charcot-Marie-Tooth disease type 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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