rs886043551

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1PM2PM5PP2BP4

The NM_006158.5(NEFL):c.22C>T(p.Pro8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P8T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEFL
NM_006158.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.60

Publications

3 publications found

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 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

NEFL links:

ENSG00000272157 (HGNC:):

ENSG00000272157 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a region_of_interest Head (size 90) in uniprot entity NFL_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_006158.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-24956494-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287020.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.31879956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFL	NM_006158.5 link	c.22C>T	p.Pro8Ser	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.22C>T	p.Pro8Ser	missense_variant	Exon 1 of 4	1	NM_006158.5	ENSP00000482169.2	P07196
ENSG00000272157	ENST00000607735.3 link	n.804G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
NEFL	ENST00000615973.1 link	n.228C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718418

African (AFR)

AF:

0.00

AC:

AN:

33218

American (AMR)

AF:

0.00

AC:

AN:

42280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25730

East Asian (EAS)

AF:

0.00

AC:

AN:

39064

South Asian (SAS)

AF:

0.00

AC:

AN:

83632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5296

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106194

Other (OTH)

AF:

0.00

AC:

AN:

59798

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2E

Uncertain:2

Jan 03, 2022

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 8 of the NEFL protein (p.Pro8Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. 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 disrupts the p.Pro8 amino acid residue in NEFL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22155564, 12566280, 28501821, 23618875, 19158810). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with NEFL-related conditions. ClinVar contains an entry for this variant (Variation ID: 576990). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.45

T;.;T

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

T;T;T

MetaRNN

Benign

0.32

T;T;T

PhyloP100

2.6

PrimateAI

Uncertain

0.59

Sift4G

Benign

0.64

T;.;T

Polyphen

0.99

D;.;.

Vest4

0.23

MVP

0.84

GERP RS

5.6

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.22

gMVP

0.80

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over