rs59101996

Variant names:

• chr8-24956070-G-A
• rs59101996
• NM_006158.5:c.446C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-24956070-G-A
• chr8-24956070-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006158.5(NEFL):​c.446C>T​(p.Ala149Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,450,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A149A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:2
• Conservation: PhyloP100: 6.85
• Publications: 8 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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFL	NM_006158.5	c.446C>T	p.Ala149Val	missense_variant	Exon 1 of 4	ENST00000610854.2	NP_006149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEFL	ENST00000610854.2	c.446C>T	p.Ala149Val	missense_variant	Exon 1 of 4	1	NM_006158.5	ENSP00000482169.2
ENSG00000272157	ENST00000607735.3	n.380G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
NEFL	ENST00000615973.1	n.652C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450908 Hom.: 0 Cov.: 37 AF XY: 0.00000277 AC XY: 2 AN XY: 721762

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85262

European-Finnish (FIN) AF: 0.0000214 AC: 1 AN: 46644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110114

Other (OTH) AF: 0.00 AC: 0 AN: 60142

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 11, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has been reported to affect NEFL protein function (PMID: 19123978). This variant has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 12477167). This variant has also been reported as c.443C>T (p.Ala148Val). ClinVar contains an entry for this variant (Variation ID: 41237). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 149 of the NEFL protein (p.Ala149Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. -

Charcot-Marie-Tooth disease type 1F Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Other:1

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Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	35
DANN	Benign	0.97
DEOGEN2	Uncertain	0.74	D;.;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.43	T;T;T
MetaRNN	Uncertain	0.66	D;D;D
PhyloP100		6.9
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.23	T;.;T
Polyphen		0.99	D;.;.
Vest4		0.52
MVP		0.78
GERP RS		5.5
Varity_R		0.65
gMVP		0.28

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: rs59101996; hg19: chr8-24813584; COSMIC: COSV55338106; COSMIC: COSV55338106;