rs59443585

chr8-24955521-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_006158.5(NEFL):c.995A>C(p.Gln332Pro) 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: 31)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.84

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a region_of_interest Coil 2B (size 115) in uniprot entity NFL_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_006158.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 8-24955521-T-G is Pathogenic according to our data. Variant chr8-24955521-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 14028.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-24955521-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEFL	NM_006158.5	c.995A>C	p.Gln332Pro	missense_variant	1/4	ENST00000610854.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFL	ENST00000610854.2	c.995A>C	p.Gln332Pro	missense_variant	1/4	1	NM_006158.5	P1
NEFL	ENST00000615973.1	n.1201A>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2E Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2016	This sequence change replaces glutamine with proline at codon 332 of the NEFL protein (p.Gln332Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with in a single family affected with Charcot-Marie-Tooth type 2 (CMT2) (PMID: 10841809) and reported in an individual affected with CMT (PMID: 27088055). This variant is also known as (c.998A>C; p.Q333P) in the literature. ClinVar contains an entry for this variant (Variation ID: 14028). Experimental studies have shown that this missense change behaved like NFL gene knockout, reducing the fusion rate, decreasing length, and enhancing motility, subsequently impaired mitochondrial transport, and NEFL Q333P caused reversible misfolding of protein and could be refolded to form coil-coiled dimers in vitro using chaotropic agent (PMID: 22155564, 23618875). In addition, motor neurons microinjected with human Q333P mutant NFL cDNAs showed fragmentation of neurites and loss of targeted motor neurons (PMID: 17881652). For these reasons, this variant has been classified as Pathogenic. -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	35
Dann	Benign	0.92
DEOGEN2	Pathogenic	0.93	D;.;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Pathogenic	0.87	D;D;D
PrimateAI	Uncertain	0.66	T
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.90
MVP		0.85
GERP RS		5.1
Varity_R		0.96
gMVP		0.97

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: rs59443585; hg19: chr8-24813035; COSMIC: COSV55337300; COSMIC: COSV55337300;