rs757417962

Variant names:

• chr8-24954233-G-A
• rs757417962
• NM_006158.5:c.1117C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-24954233-G-A
• chr8-24954233-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006158.5(NEFL):​c.1117C>T​(p.Gln373*) variant causes a stop gained 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEFL NM_006158.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.97
• Publications: 0 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-24954233-G-A is Pathogenic according to our data. Variant chr8-24954233-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 533513.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFL	NM_006158.5	c.1117C>T	p.Gln373*	stop_gained	Exon 2 of 4	ENST00000610854.2	NP_006149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEFL	ENST00000610854.2	c.1117C>T	p.Gln373*	stop_gained	Exon 2 of 4	1	NM_006158.5	ENSP00000482169.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2E Pathogenic:1

Feb 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with NEFL-related disease. ClinVar contains an entry for this variant (Variation ID: 533513). This sequence change creates a premature translational stop signal (p.Gln373*) in the NEFL gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in NEFL are known to be pathogenic (PMID: 19158810, 20039262). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	42
DANN	Benign	0.91
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
Vest4		0.98
GERP RS		6.1

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: rs757417962; hg19: chr8-24811747;