rs876657412

Positions:

• chr22-29490656-A-AAGCC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_021076.4(NEFH):​c.3017_3020dup​(p.Pro1008AlafsTer56) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. K1006K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEFH NM_021076.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.00700

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 Uncertain_significance. Variant got 5 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 0.0153 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 22-29490656-A-AAGCC is Pathogenic according to our data. Variant chr22-29490656-A-AAGCC is described in ClinVar as [Pathogenic]. Clinvar id is 225631.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEFH	NM_021076.4	c.3017_3020dup	p.Pro1008AlafsTer56	frameshift_variant	4/4	ENST00000310624.7
NEFH	XM_011530200.3	c.2729_2732dup	p.Pro912AlafsTer56	frameshift_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFH	ENST00000310624.7	c.3017_3020dup	p.Pro1008AlafsTer56	frameshift_variant	4/4	1	NM_021076.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876657412; hg19: chr22-29886645;