8-24955888-C-T

Variant names:

• chr8-24955888-C-T
• rs199422214
• NM_006158.5:c.628G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_006158.5(NEFL):​c.628G>A​(p.Glu210Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,454,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. E210Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09
• Publications: 0 publications found

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]

NEFL Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 1F

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease type 2E

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 2B5

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000272157 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 0.63774 (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease type 2B5, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1F.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006158.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFL	NM_006158.5	MANE Select	c.628G>A	p.Glu210Lys	missense	Exon 1 of 4	NP_006149.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFL	ENST00000610854.2	TSL:1 MANE Select	c.628G>A	p.Glu210Lys	missense	Exon 1 of 4	ENSP00000482169.2
	ENSG00000272157	ENST00000607735.3	TSL:6	n.198C>T		non_coding_transcript_exon	Exon 1 of 1
	NEFL	ENST00000615973.1	TSL:6	n.834G>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454284 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 723914

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Pathogenic	0.87	D
PhyloP100		6.1
PrimateAI	Uncertain	0.73	T
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.79
GERP RS		5.7
Varity_R		0.76
gMVP		0.75

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

Other links and lift over

dbSNP: rs199422214; hg19: chr8-24813402;