NM_006158.5:c.1610A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_006158.5(NEFL):c.1610A>G(p.Gln537Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000826 in 1,613,712 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q537Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 1 hom. )

Consequence

NEFL
NM_006158.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 0.707

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

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=0.035324752).

BP6

Variant 8-24952832-T-C is Benign according to our data. Variant chr8-24952832-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220209.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000538 (82/152334) while in subpopulation NFE AF = 0.000926 (63/68028). AF 95% confidence interval is 0.000742. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFL	NM_006158.5 link	c.1610A>G	p.Gln537Arg	missense_variant	Exon 4 of 4	ENST00000610854.2	NP_006149.2	P07196

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEFL	ENST00000610854.2 link	c.1610A>G	p.Gln537Arg	missense_variant	Exon 4 of 4	1	NM_006158.5	ENSP00000482169.2		P07196

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000433

AC:

108

AN:

249264

AF XY:

0.000422

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000646

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.000856

AC:

1251

AN:

1461378

Hom.:

Cov.:

AF XY:

0.000840

AC XY:

611

AN XY:

726990

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33474

American (AMR)

AF:

0.000827

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000998

AC:

1109

AN:

1111610

Other (OTH)

AF:

0.00159

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000538

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41574

American (AMR)

AF:

0.000784

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000926

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000655

Hom.:

Bravo

AF:

0.000540

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000527

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.000347

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEFL: PM2:Supporting, BP4 -

Jun 30, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in an individual with congenital hypotonia; however, this individual was found to have two truncating variants on opposite alleles of the IGHMBP2 gene (PMID: 26257172); Reported previously as a variant of uncertain significance in three patients with suspected Charcot-Marie-Tooth disease; however, no further clinical or segregation information was provided (PMID: 32376792); In silico analysis does not support a benign or deleterious effect of this variant on protein structure/function; This variant is associated with the following publications: (PMID: 28501821, 26257172, 32376792) -

Apr 14, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 30, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q537R variant (also known as c.1610A>G), located in coding exon 4 of the NEFL gene, results from an A to G substitution at nucleotide position 1610. The glutamine at codon 537 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant Charcot-Marie-Tooth disease; however, its contribution to the development of autosomal recessive CMT is uncertain. -

Charcot-Marie-Tooth disease type 1F;C1843225:Charcot-Marie-Tooth disease type 2E;C4693509:Charcot-Marie-Tooth disease, dominant intermediate G

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 30, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2E

Benign:1

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.36

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.38

MetaRNN

Benign

0.035

PhyloP100

0.71

PrimateAI

Benign

0.38

Sift4G

Benign

0.25

Polyphen

0.0

Vest4

0.054

MVP

0.71

GERP RS

3.5

Varity_R

0.082

gMVP

0.0039

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over