rs59101996
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000610854.2(NEFL):c.446C>T(p.Ala149Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,450,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A149A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
NEFL
ENST00000610854.2 missense
ENST00000610854.2 missense
Scores
1
5
4
Clinical Significance
Conservation
PhyloP100: 6.85
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEFL | NM_006158.5 | c.446C>T | p.Ala149Val | missense_variant | 1/4 | ENST00000610854.2 | NP_006149.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEFL | ENST00000610854.2 | c.446C>T | p.Ala149Val | missense_variant | 1/4 | 1 | NM_006158.5 | ENSP00000482169 | P1 | |
ENST00000607735.2 | n.130G>A | non_coding_transcript_exon_variant | 1/1 | |||||||
NEFL | ENST00000615973.1 | n.652C>T | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1450908Hom.: 0 Cov.: 37 AF XY: 0.00000277 AC XY: 2AN XY: 721762
GnomAD4 exome
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2
AN:
1450908
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Cov.:
37
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2
AN XY:
721762
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 2E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 11, 2020 | This sequence change replaces alanine with valine at codon 149 of the NEFL protein (p.Ala149Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 12477167). This variant has also been reported as c.443C>T (p.Ala148Val). ClinVar contains an entry for this variant (Variation ID: 41237). This variant has been reported to affect NEFL protein function (PMID: 19123978). 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. - |
Charcot-Marie-Tooth disease type 1F Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
DEOGEN2
Uncertain
D;.;T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
MetaRNN
Uncertain
D;D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;.;T
Polyphen
D;.;.
Vest4
MVP
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at