rs165602

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021076.4(NEFH):c.2414A>C(p.Glu805Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,613,862 control chromosomes in the GnomAD database, including 20,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E805V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.14 ( 1785 hom., cov: 31)

Exomes 𝑓: 0.16 ( 18654 hom. )

Consequence

NEFH
NM_021076.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 3.57

Publications

37 publications found

Variant links:

Genes affected

NEFH (HGNC:7737): (neurofilament heavy chain) Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and functionally maintain neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the heavy neurofilament protein. This protein is commonly used as a biomarker of neuronal damage and susceptibility to amyotrophic lateral sclerosis (ALS) has been associated with mutations in this gene. [provided by RefSeq, Oct 2008]

NEFH Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2CC
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NEFH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014665723).

BP6

Variant 22-29490054-A-C is Benign according to our data. Variant chr22-29490054-A-C is described in ClinVar as Benign. ClinVar VariationId is 66741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFH	NM_021076.4 link	c.2414A>C	p.Glu805Ala	missense_variant	Exon 4 of 4	ENST00000310624.7	NP_066554.2	P12036
NEFH	XM_011530200.3 link	c.2126A>C	p.Glu709Ala	missense_variant	Exon 5 of 5		XP_011528502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEFH	ENST00000310624.7 link	c.2414A>C	p.Glu805Ala	missense_variant	Exon 4 of 4	1	NM_021076.4	ENSP00000311997.6		P12036

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

21956

AN:

151934

Hom.:

1784

Cov.:

show subpopulations

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.0934

Gnomad EAS

AF:

0.0465

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.126

GnomAD2 exomes

AF:

0.151

AC:

37943

AN:

250792

AF XY:

0.154

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.0928

Gnomad EAS exome

AF:

0.0454

Gnomad FIN exome

AF:

0.249

Gnomad NFE exome

AF:

0.157

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.156

AC:

228065

AN:

1461810

Hom.:

18654

Cov.:

AF XY:

0.157

AC XY:

113951

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.112

AC:

3757

AN:

33478

American (AMR)

AF:

0.130

AC:

5833

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0954

AC:

2493

AN:

26136

East Asian (EAS)

AF:

0.0323

AC:

1283

AN:

39696

South Asian (SAS)

AF:

0.178

AC:

15388

AN:

86258

European-Finnish (FIN)

AF:

0.252

AC:

13475

AN:

53418

Middle Eastern (MID)

AF:

0.104

AC:

602

AN:

5768

European-Non Finnish (NFE)

AF:

0.159

AC:

176355

AN:

1111960

Other (OTH)

AF:

0.147

AC:

8879

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

12464

24927

37391

49854

62318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6184

12368

18552

24736

30920

<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:

0.144

AC:

21967

AN:

152052

Hom.:

1785

Cov.:

AF XY:

0.149

AC XY:

11072

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.118

AC:

4898

AN:

41508

American (AMR)

AF:

0.113

AC:

1723

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0934

AC:

324

AN:

3470

East Asian (EAS)

AF:

0.0460

AC:

237

AN:

5152

South Asian (SAS)

AF:

0.173

AC:

830

AN:

4810

European-Finnish (FIN)

AF:

0.260

AC:

2755

AN:

10586

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.158

AC:

10729

AN:

67940

Other (OTH)

AF:

0.124

AC:

261

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

947

1894

2842

3789

4736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.138

Hom.:

3327

Bravo

AF:

0.132

TwinsUK

AF:

0.153

AC:

567

ALSPAC

AF:

0.155

AC:

599

ESP6500AA

AF:

0.129

AC:

567

ESP6500EA

AF:

0.153

AC:

1313

ExAC

AF:

0.153

AC:

18574

EpiCase

AF:

0.146

EpiControl

AF:

0.136

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Amyotrophic lateral sclerosis type 1

Benign:2

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2CC

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.87

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.86

PhyloP100

3.6

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.38

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Vest4

0.093

MPC

0.11

ClinPred

0.036

GERP RS

5.4

gMVP

0.054

Mutation Taster

=90/10

polymorphism (auto)

(source)

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