8-24956223-T-C

Variant names:

• chr8-24956223-T-C
• rs58982919
• NM_006158.5:c.293A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_006158.5(NEFL):​c.293A>G​(p.Asn98Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000279221: Published functional studies in an animal model indicate that the N98S substitution results in a significant reduction in the number of neurofilaments, reduced axonal diameters, and in distal axon loss in the peripheral nervous system (Adebola et al., 2015" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N98D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1 O:2
• Conservation: PhyloP100: 7.93
• Publications: 44 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: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000279221: Published functional studies in an animal model indicate that the N98S substitution results in a significant reduction in the number of neurofilaments, reduced axonal diameters, and in distal axon loss in the peripheral nervous system (Adebola et al., 2015; Zhao et al., 2017; Lancaster et al., 2018);; SCV000639659: Experimental studies have shown that this missense change affects NEFL function (PMID: 25448007, 25552649).; SCV004101323: Motor neurons derived from patient induced pluripotent stem cells show abnormalities in cytoskeletal structure, mitochondrial trafficking, and electrophysiological properties (PMID: 25448007). A knock-in mouse model of the p.Asn98Ser variant also shows tremor as well as cellular features of neuropathy (PMID: 25448007).; SCV004848847: Animal models in mice have shown that this variant causes Charcot-Marie-Tooth disease (Adebola 2015 PMID: 25552649, Saporta 2015 PMID: 25448007).; SCV002012110: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product." PMID: 25552649
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_006158.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-24956224-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2664371.
• 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 1F, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease type 2B5.
• PP5: Variant 8-24956223-T-C is Pathogenic according to our data. Variant chr8-24956223-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 41236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFL	NM_006158.5	MANE Select	c.293A>G	p.Asn98Ser	missense	Exon 1 of 4	NP_006149.2	P07196

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFL	ENST00000610854.2	TSL:1 MANE Select	c.293A>G	p.Asn98Ser	missense	Exon 1 of 4	ENSP00000482169.2	P07196
	NEFL	ENST00000916556.1		c.293A>G	p.Asn98Ser	missense	Exon 1 of 4	ENSP00000586615.1
	ENSG00000272157	ENST00000607735.3	TSL:6	n.533T>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000863 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	1	-	Charcot-Marie-Tooth disease (4)
2	-	-	Charcot-Marie-Tooth disease type 1F (3)
2	-	-	not provided (3)
1	-	-	Charcot-Marie-Tooth disease type 1F;C1843225:Charcot-Marie-Tooth disease type 2E;C4693509:Charcot-Marie-Tooth disease, dominant intermediate G (1)
1	-	-	Charcot-Marie-Tooth disease type 2E (1)
1	-	-	Charcot-Marie-Tooth disease, dominant intermediate G (1)
1	-	-	Developmental disorder;C0018784:Sensorineural hearing loss disorder (1)
1	-	-	NEFL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	35
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Uncertain	0.67	D
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.80
GERP RS		5.3
PromoterAI		-0.084	Neutral
Varity_R		0.86
gMVP		0.87

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: rs58982919; hg19: chr8-24813737;