rs771234852
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_181882.3(PRX):c.4246_4247insTGT(p.Val1415_Ser1416insLeu) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,609,186 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 1 hom. )
Consequence
PRX
NM_181882.3 inframe_insertion
NM_181882.3 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.131
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 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_181882.3. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.4246_4247insTGT | p.Val1415_Ser1416insLeu | inframe_insertion | 7/7 | ENST00000324001.8 | |
PRX | NM_001411127.1 | c.4531_4532insTGT | p.Val1510_Ser1511insLeu | inframe_insertion | 7/7 | ||
PRX | XM_017027047.2 | c.4144_4145insTGT | p.Val1381_Ser1382insLeu | inframe_insertion | 4/4 | ||
PRX | NM_020956.2 | c.*4451_*4452insTGT | 3_prime_UTR_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRX | ENST00000324001.8 | c.4246_4247insTGT | p.Val1415_Ser1416insLeu | inframe_insertion | 7/7 | 1 | NM_181882.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000213 AC: 53AN: 249318Hom.: 0 AF XY: 0.000297 AC XY: 40AN XY: 134774
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GnomAD4 exome AF: 0.000133 AC: 194AN: 1457044Hom.: 1 Cov.: 30 AF XY: 0.000178 AC XY: 129AN XY: 723972
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 31, 2020 | In-frame insertion of 1 amino acid in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 30, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 26, 2019 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2020 | The c.4244_4246dupTGT variant (also known as p.V1415_S1416insL), located in coding exon 4 of the PRX gene, results from an in-frame insertion of TGT due to the duplication of nucleotides 4244 through 4246. This results in the insertion of an extra residue (L) between codon 1415 and codon 1416. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at