rs201792838
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The ENST00000324001.8(PRX):c.2775C>T(p.Val925=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000514 in 1,614,182 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00053 ( 6 hom. )
Consequence
PRX
ENST00000324001.8 synonymous
ENST00000324001.8 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.369
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=-0.56).
BP6
Variant 19-40395577-G-A is Benign according to our data. Variant chr19-40395577-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 329262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40395577-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.369 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000381 (58/152300) while in subpopulation SAS AF= 0.0114 (55/4828). AF 95% confidence interval is 0.00899. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 6 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.2775C>T | p.Val925= | synonymous_variant | 7/7 | ENST00000324001.8 | NP_870998.2 | |
PRX | NM_001411127.1 | c.3060C>T | p.Val1020= | synonymous_variant | 7/7 | NP_001398056.1 | ||
PRX | XM_017027047.2 | c.2673C>T | p.Val891= | synonymous_variant | 4/4 | XP_016882536.1 | ||
PRX | NM_020956.2 | c.*2980C>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.2775C>T | p.Val925= | synonymous_variant | 7/7 | 1 | NM_181882.3 | ENSP00000326018 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000381 AC: 58AN: 152182Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00117 AC: 294AN: 251474Hom.: 3 AF XY: 0.00155 AC XY: 210AN XY: 135918
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GnomAD4 exome AF: 0.000527 AC: 771AN: 1461882Hom.: 6 Cov.: 99 AF XY: 0.000714 AC XY: 519AN XY: 727242
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GnomAD4 genome AF: 0.000381 AC: 58AN: 152300Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44AN XY: 74480
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2018 | 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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Charcot-Marie-Tooth disease type 4F Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
not provided Benign:1
Likely 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 | Jan 27, 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