rs777104457
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_181882.3(PRX):āc.1500A>Gā(p.Ser500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,458,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000060 ( 0 hom., cov: 33)
Exomes š: 0.000045 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PRX
NM_181882.3 synonymous
NM_181882.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -7.85
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 Likely_benign. Variant got -4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.94).
BP6
?
Variant 19-40396852-T-C is Benign according to our data. Variant chr19-40396852-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329276.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr19-40396852-T-C is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-7.85 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.1500A>G | p.Ser500= | synonymous_variant | 7/7 | ENST00000324001.8 | |
PRX | NM_001411127.1 | c.1785A>G | p.Ser595= | synonymous_variant | 7/7 | ||
PRX | XM_017027047.2 | c.1398A>G | p.Ser466= | synonymous_variant | 4/4 | ||
PRX | NM_020956.2 | c.*1705A>G | 3_prime_UTR_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRX | ENST00000324001.8 | c.1500A>G | p.Ser500= | synonymous_variant | 7/7 | 1 | NM_181882.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000596 AC: 9AN: 150932Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250856Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135728
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GnomAD4 exome AF: 0.0000446 AC: 65AN: 1458082Hom.: 0 Cov.: 36 AF XY: 0.0000496 AC XY: 36AN XY: 725174
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000596 AC: 9AN: 150932Hom.: 0 Cov.: 33 AF XY: 0.0000543 AC XY: 4AN XY: 73676
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 4F Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
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 | Aug 05, 2016 | 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 4 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 05, 2023 | - - |
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