rs779821785

chr8-24956458-C-Gchr8-24956458-C-T

Variant summary

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

The NM_006158.5(NEFL):c.58G>C(p.Glu20Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,451,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E20K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17

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 region_of_interest Head (size 90) in uniprot entity NFL_HUMAN there are 25 pathogenic changes around while only 5 benign (83%) in NM_006158.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.3704189).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEFL	NM_006158.5	c.58G>C	p.Glu20Gln	missense_variant	1/4	ENST00000610854.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFL	ENST00000610854.2	c.58G>C	p.Glu20Gln	missense_variant	1/4	1	NM_006158.5	P1
	ENST00000607735.2	n.518C>G		non_coding_transcript_exon_variant	1/1
NEFL	ENST00000615973.1	n.264G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000438 AC: 1 AN: 228522 Hom.: 0 AF XY: 0.00000803 AC XY: 1 AN XY: 124596

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: 0.00000971

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1451950 Hom.: 0 Cov.: 36 AF XY: 0.00000693 AC XY: 5 AN XY: 721276

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Benign	0.95
DEOGEN2	Uncertain	0.64	D;.;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.37	T;T;T
PrimateAI	Uncertain	0.69	T
Sift4G	Uncertain	0.057	T;.;T
Polyphen		0.59	P;.;.
Vest4		0.25
MVP		0.82
GERP RS		5.3
Varity_R		0.50
gMVP		0.68

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: rs779821785; hg19: chr8-24813972;