rs62636503

Positions:

• chr8-24953779-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other: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

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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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	32
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Pathogenic	0.96	D
PrimateAI	Pathogenic	0.83	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.81
GERP RS		5.9
Varity_R		0.66
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs62636503; hg19: chr8-24811293;