dbSNP rs59101996: NEFL:p.Ala149Val (chr8-24956070-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NEFL
NM_006158.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:2

Conservation

PhyloP100: 6.85

Variant links:

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 links:

ENSG00000272157 (HGNC:):

ENSG00000272157 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFL	NM_006158.5 link	c.446C>T	p.Ala149Val	missense_variant	Exon 1 of 4	ENST00000610854.2	NP_006149.2	P07196

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEFL	ENST00000610854.2 link	c.446C>T	p.Ala149Val	missense_variant	Exon 1 of 4	1	NM_006158.5	ENSP00000482169.2	P07196
ENSG00000272157	ENST00000607735.2 link	n.130G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
NEFL	ENST00000615973.1 link	n.652C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450908

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721762

show subpopulations

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:

0.0000117

Gnomad4 FIN exome

AF:

0.0000214

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:2

Revision: criteria provided, single submitter

LINK: link

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

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided

Other:1

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

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Uncertain

0.74

D;.;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.43

T;T;T

MetaRNN

Uncertain

0.66

D;D;D

PrimateAI

Uncertain

0.55

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over