rs62636503
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_006158.5(NEFL):c.1186G>A(p.Glu396Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
NEFL
NM_006158.5 missense
NM_006158.5 missense
Scores
8
1
1
Clinical Significance
Conservation
PhyloP100: 7.62
Genes affected
NEFL (HGNC:7739): (neurofilament light chain) Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and they functionally maintain the neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the light chain neurofilament protein. Mutations in this gene cause Charcot-Marie-Tooth disease types 1F (CMT1F) and 2E (CMT2E), disorders of the peripheral nervous system that are characterized by distinct neuropathies. A pseudogene has been identified on chromosome Y. [provided by RefSeq, Oct 2008]
MIR6841 (HGNC:50070): (microRNA 6841) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_006158.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.956
PP5
?
Variant 8-24953779-C-T is Pathogenic according to our data. Variant chr8-24953779-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 66671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-24953779-C-T is described in Lovd as [Pathogenic]. Variant chr8-24953779-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEFL | NM_006158.5 | c.1186G>A | p.Glu396Lys | missense_variant | 3/4 | ENST00000610854.2 | |
MIR6841 | NR_106900.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEFL | ENST00000610854.2 | c.1186G>A | p.Glu396Lys | missense_variant | 3/4 | 1 | NM_006158.5 | P1 | |
MIR6841 | ENST00000637129.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 12, 2022 | Published functional studies demonstrate a damaging effect resulting in sensory changes and NF organization being altered in motor and sensory roots (Villaln et al., 2017; Shen et al., 2011); Not observed in large population cohorts (gnomAD); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 19158810, 20039262, 26645395, 18023247, 35044100, 17052987, 15241803, 21493625, 14733962, 22206013, 27040688, 25877835, 26109717, 22288874, 23412702, 27549087, 27862672, 31211173, 31701603, 31574566, 30569449, 31715019, 29191368, 24887401, 27643807, 32376792) - |
Charcot-Marie-Tooth disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease type 2E Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 396 of the NEFL protein (p.Glu396Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (CMT) (PMID: 14733962, 17052987, 19158810, 22206013, 24887401, 25877835, 26109717, 27549087). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Glu397Lys. ClinVar contains an entry for this variant (Variation ID: 66671). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NEFL protein function. Experimental studies have shown that this missense change affects NEFL function (PMID: 21493625, 22288874). - |
Charcot-Marie-Tooth disease, dominant intermediate G Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Pathogenic
D
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
MetaRNN
Pathogenic
D
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at