rs876657411

Positions:

• chr22-29490648-AAG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The ENST00000310624.7(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 ENST00000310624.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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]

ACMG classification

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	Protein	UniProt
NEFH	NM_021076.4	c.3010_3011del	p.Asp1004GlnfsTer58	frameshift_variant	4/4	ENST00000310624.7	NP_066554.2
NEFH	XM_011530200.3	c.2722_2723del	p.Asp908GlnfsTer58	frameshift_variant	5/5		XP_011528502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEFH	ENST00000310624.7	c.3010_3011del	p.Asp1004GlnfsTer58	frameshift_variant	4/4	1	NM_021076.4	ENSP00000311997	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Charcot-Marie-Tooth disease axonal type 2CC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657411; hg19: chr22-29886637;