rs59371099

chr22-29489027-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 4.66

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]

ACMG classification

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	UniProt
NEFH	NM_021076.4	c.1387G>A	p.Glu463Lys	missense_variant	4/4	ENST00000310624.7
NEFH	XM_011530200.3	c.1387G>A	p.Glu463Lys	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFH	ENST00000310624.7	c.1387G>A	p.Glu463Lys	missense_variant	4/4	1	NM_021076.4	P1

Frequencies

GnomAD3 genomes AF: 0.0668 AC: 10158 AN: 152128 Hom.: 476 Cov.: 32

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

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.: 34 AF XY: 0.0805 AC XY: 58529 AN XY: 727202

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.: 32 AF XY: 0.0662 AC XY: 4926 AN XY: 74428

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: 69

ESP6500EA AF: 0.0981 AC: 844

ExAC AF: 0.0684 AC: 8302

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
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, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 28, 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	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.3e-8	P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.12	T
Vest4		0.23
MPC		0.12
ClinPred		0.014	T
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

Other links and lift over

dbSNP: rs59371099; hg19: chr22-29885016; COSMIC: COSV60217188;