Variant rs59371099 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021076.4(NEFH):c.1387G>A(p.Glu463Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0796 in 1,614,054 control chromosomes in the GnomAD database, including 5,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.067 ( 477 hom., cov: 32)

Exomes 𝑓: 0.081 ( 5333 hom. )

Consequence

NEFH
NM_021076.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 4.66

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00260517).

BP6

Variant 22-29489027-G-A is Benign according to our data. Variant chr22-29489027-G-A is described in ClinVar as [Benign]. Clinvar id is 66729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-29489027-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEFH	NM_021076.4 link	c.1387G>A	p.Glu463Lys	missense_variant	4/4	ENST00000310624.7	NP_066554.2	P12036
NEFH	XM_011530200.3 link	c.1387G>A	p.Glu463Lys	missense_variant	4/5		XP_011528502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEFH	ENST00000310624.7 link	c.1387G>A	p.Glu463Lys	missense_variant	4/4	1	NM_021076.4	ENSP00000311997.6		P12036

Frequencies

GnomAD3 genomes

AF:

0.0668

AC:

10158

AN:

152128

Hom.:

476

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.0737

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0232

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0953

Gnomad OTH

AF:

0.0746

GnomAD3 exomes

AF:

0.0705

AC:

17712

AN:

251308

Hom.:

838

AF XY:

0.0710

AC XY:

9648

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.0134

Gnomad AMR exome

AF:

0.0541

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0229

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0956

Gnomad OTH exome

AF:

0.0856

GnomAD4 exome

AF:

0.0809

AC:

118332

AN:

1461808

Hom.:

5333

Cov.:

AF XY:

0.0805

AC XY:

58529

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0130

Gnomad4 AMR exome

AF:

0.0553

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0227

Gnomad4 FIN exome

AF:

0.106

Gnomad4 NFE exome

AF:

0.0897

Gnomad4 OTH exome

AF:

0.0786

GnomAD4 genome

AF:

0.0667

AC:

10158

AN:

152246

Hom.:

477

Cov.:

AF XY:

0.0662

AC XY:

4926

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0141

Gnomad4 AMR

AF:

0.0736

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.000577

Gnomad4 SAS

AF:

0.0237

Gnomad4 FIN

AF:

0.110

Gnomad4 NFE

AF:

0.0953

Gnomad4 OTH

AF:

0.0739

Alfa

AF:

0.0849

Hom.:

280

Bravo

AF:

0.0631

TwinsUK

AF:

0.0979

AC:

363

ALSPAC

AF:

0.0846

AC:

326

ESP6500AA

AF:

0.0157

AC:

ESP6500EA

AF:

0.0981

AC:

844

ExAC

AF:

0.0684

AC:

8302

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 30180840) -

Amyotrophic lateral sclerosis type 1

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.52

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.53

Sift

Uncertain

0.0050

Sift4G

Benign

0.12

Vest4

0.23

MPC

0.12

ClinPred

0.014

GERP RS

5.8

gMVP

0.77

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