chr8-24956449-G-C

Position:

• chr8-24956449-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_006158.5(NEFL):​c.67C>G​(p.Arg23Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,451,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.17

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a modified_residue Omega-N-methylarginine; alternate (size 0) in uniprot entity NFL_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.4085758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEFL	NM_006158.5	c.67C>G	p.Arg23Gly	missense_variant	1/4	ENST00000610854.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFL	ENST00000610854.2	c.67C>G	p.Arg23Gly	missense_variant	1/4	1	NM_006158.5	P1
	ENST00000607735.2	n.509G>C		non_coding_transcript_exon_variant	1/1
NEFL	ENST00000615973.1	n.273C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000874 AC: 2 AN: 228796 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124722

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000970

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1451874 Hom.: 0 Cov.: 36 AF XY: 0.00000555 AC XY: 4 AN XY: 721232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2020

The p.R23G variant (also known as c.67C>G), located in coding exon 1 of the NEFL gene, results from a C to G substitution at nucleotide position 67. The arginine at codon 23 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported in a heterozygous state in an individual with CMT2, as well as the unaffected mother. Functional analysis was not performed on any identified alteration. (Bacquet J et al. BMJ Open, 2018 10;8:e021632). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2E Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 25, 2023

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 23 of the NEFL protein (p.Arg23Gly). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 30373780). ClinVar contains an entry for this variant (Variation ID: 569562). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NEFL protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.78	D;.;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.41	T;T;T
PrimateAI	Uncertain	0.64	T
Sift4G	Uncertain	0.012	D;.;D
Polyphen		0.81	P;.;.
Vest4		0.31
MVP		0.77
GERP RS		5.3
Varity_R		0.75
gMVP		0.87

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: rs772092001; hg19: chr8-24813963;