rs373569840
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_006158.5(NEFL):c.755C>T(p.Pro252Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,613,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )
Consequence
NEFL
NM_006158.5 missense
NM_006158.5 missense
Scores
5
5
Clinical Significance
Conservation
PhyloP100: 7.95
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEFL | NM_006158.5 | c.755C>T | p.Pro252Leu | missense_variant | 1/4 | ENST00000610854.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEFL | ENST00000610854.2 | c.755C>T | p.Pro252Leu | missense_variant | 1/4 | 1 | NM_006158.5 | P1 | |
NEFL | ENST00000615973.1 | n.961C>T | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248378Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134838
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GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461166Hom.: 0 Cov.: 37 AF XY: 0.0000289 AC XY: 21AN XY: 726896
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74322
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 10, 2020 | The p.P252L variant (also known as c.755C>T), located in coding exon 1 of the NEFL gene, results from a C to T substitution at nucleotide position 755. The proline at codon 252 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 2E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 252 of the NEFL protein (p.Pro252Leu). This variant is present in population databases (rs373569840, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of NEFL-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 569117). 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 with a positive predictive value of 80%. 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
MetaRNN
Uncertain
D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at