NM_006158.5:c.23C>A
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PM1PM2PM5PP2PP5_ModerateBP4
The NM_006158.5(NEFL):c.23C>A(p.Pro8Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P8T) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NEFL
NM_006158.5 missense
NM_006158.5 missense
Scores
6
4
Clinical Significance
Conservation
PhyloP100: 2.76
Publications
22 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 diseaseInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- Charcot-Marie-Tooth disease type 2Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Charcot-Marie-Tooth disease type 1FInheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
- Charcot-Marie-Tooth disease type 2EInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Charcot-Marie-Tooth disease type 2B5Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
PM1
In a region_of_interest Head (size 90) in uniprot entity NFL_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) 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 chr8-24956494-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287020.
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.
PP5
Variant 8-24956493-G-T is Pathogenic according to our data. Variant chr8-24956493-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 66687.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.35497838). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NEFL | ENST00000610854.2 | c.23C>A | p.Pro8Gln | missense_variant | Exon 1 of 4 | 1 | NM_006158.5 | ENSP00000482169.2 | ||
| ENSG00000272157 | ENST00000607735.3 | n.803G>T | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 | |||||
| NEFL | ENST00000615973.1 | n.229C>A | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1447836Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 718908
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1447836
Hom.:
Cov.:
36
AF XY:
AC XY:
0
AN XY:
718908
African (AFR)
AF:
AC:
0
AN:
33242
American (AMR)
AF:
AC:
0
AN:
42414
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25732
East Asian (EAS)
AF:
AC:
0
AN:
39098
South Asian (SAS)
AF:
AC:
0
AN:
83728
European-Finnish (FIN)
AF:
AC:
0
AN:
51916
Middle Eastern (MID)
AF:
AC:
0
AN:
5344
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1106528
Other (OTH)
AF:
AC:
0
AN:
59834
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease Pathogenic:1
-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
not provided Other:1
-
Epithelial Biology; Institute of Medical Biology, Singapore
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
DANN
Benign
DEOGEN2
Uncertain
T;.;T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
MetaRNN
Benign
T;T;T
PhyloP100
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
Publications
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