rs59371099

Variant names:

• chr22-29489027-G-A
• rs59371099
• NM_021076.4:c.1387G>A

Variant summary

Our verdict is Benign. The variant received -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:7 O:1
• Conservation: PhyloP100: 4.66
• Publications: 18 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 66729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0933 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021076.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFH	NM_021076.4	MANE Select	c.1387G>A	p.Glu463Lys	missense	Exon 4 of 4	NP_066554.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFH	ENST00000310624.7	TSL:1 MANE Select	c.1387G>A	p.Glu463Lys	missense	Exon 4 of 4	ENSP00000311997.6	P12036-1

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

GnomAD2 exomes AF: 0.0705 AC: 17712 AN: 251308 AF XY: 0.0710

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 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

African (AFR) AF: 0.0130 AC: 435 AN: 33480

American (AMR) AF: 0.0553 AC: 2471 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2911 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39686

South Asian (SAS) AF: 0.0227 AC: 1956 AN: 86254

European-Finnish (FIN) AF: 0.106 AC: 5668 AN: 53418

Middle Eastern (MID) AF: 0.0739 AC: 426 AN: 5766

European-Non Finnish (NFE) AF: 0.0897 AC: 99712 AN: 1111958

Other (OTH) AF: 0.0786 AC: 4749 AN: 60394

GnomAD4 genome AF: 0.0667 AC: 10158 AN: 152246 Hom.: 477 Cov.: 32 AF XY: 0.0662 AC XY: 4926 AN XY: 74428

African (AFR) AF: 0.0141 AC: 588 AN: 41560

American (AMR) AF: 0.0736 AC: 1126 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3470

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5196

South Asian (SAS) AF: 0.0237 AC: 114 AN: 4820

European-Finnish (FIN) AF: 0.110 AC: 1170 AN: 10596

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.0953 AC: 6477 AN: 67994

Other (OTH) AF: 0.0739 AC: 156 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	Amyotrophic lateral sclerosis type 1 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
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
PhyloP100		4.7
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
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

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