8-24956227-G-T

Variant names:

• chr8-24956227-G-T
• rs587777888
• NM_006158.5:c.289C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_006158.5(NEFL):​c.289C>A​(p.Leu97Ile) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L97P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.01
• Publications: 2 publications found

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]

NEFL Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 1F

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease type 2E

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 2B5

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000272157 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_006158.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 0.63774 (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease type 2B5, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1F.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006158.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFL	NM_006158.5	MANE Select	c.289C>A	p.Leu97Ile	missense	Exon 1 of 4	NP_006149.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFL	ENST00000610854.2	TSL:1 MANE Select	c.289C>A	p.Leu97Ile	missense	Exon 1 of 4	ENSP00000482169.2
	ENSG00000272157	ENST00000607735.3	TSL:6	n.537G>T		non_coding_transcript_exon	Exon 1 of 1
	NEFL	ENST00000615973.1	TSL:6	n.495C>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with NEFL-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with isoleucine at codon 97 of the NEFL protein (p.Leu97Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.85	D
PhyloP100		8.0
PrimateAI	Pathogenic	0.81	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.53
GERP RS		5.3
PromoterAI		0.034	Neutral
Varity_R		0.87
gMVP		0.68

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

Other links and lift over

dbSNP: rs587777888; hg19: chr8-24813741;