rs876657411
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_021076.4(NEFH):c.3010_3011del(p.Asp1004GlnfsTer58) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
NEFH
NM_021076.4 frameshift
NM_021076.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.18
Genes affected
NEFH (HGNC:7737): (neurofilament heavy chain) Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and functionally maintain neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the heavy neurofilament protein. This protein is commonly used as a biomarker of neuronal damage and susceptibility to amyotrophic lateral sclerosis (ALS) has been associated with mutations in this gene. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0176 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 22-29490648-AAG-A is Pathogenic according to our data. Variant chr22-29490648-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 225630.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEFH | NM_021076.4 | c.3010_3011del | p.Asp1004GlnfsTer58 | frameshift_variant | 4/4 | ENST00000310624.7 | |
NEFH | XM_011530200.3 | c.2722_2723del | p.Asp908GlnfsTer58 | frameshift_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEFH | ENST00000310624.7 | c.3010_3011del | p.Asp1004GlnfsTer58 | frameshift_variant | 4/4 | 1 | NM_021076.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2CC Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 24, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 08, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the NEFH protein. Other variant(s) that result in a similarly extended protein product (p.Lys1020Glufs*43) have been determined to be pathogenic (PMID: 29587262, 30992180; Invitae). This suggests that these extensions are likely to be disease-causing. Experimental studies have shown that this frameshift affects NEFH function (PMID: 27040688). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 225630). This frameshift has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 27040688). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the NEFH gene (p.Asp1004Glnfs*58). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the NEFH protein and extend the protein by 40 additional amino acid residues. - |
Computational scores
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Calibrated prediction
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Prediction
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