rs165602

chr22-29490054-A-Cchr22-29490054-A-T

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.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 same amino acid change has been previously reported as Uncertain significancein 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.57

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=0.0014665723).
• BP6: Variant 22-29490054-A-C is Benign according to our data. Variant chr22-29490054-A-C is described in ClinVar as [Benign]. Clinvar id is 66741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-29490054-A-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
NEFH	NM_021076.4	c.2414A>C	p.Glu805Ala	missense_variant	4/4	ENST00000310624.7
NEFH	XM_011530200.3	c.2126A>C	p.Glu709Ala	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFH	ENST00000310624.7	c.2414A>C	p.Glu805Ala	missense_variant	4/4	1	NM_021076.4	P1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 21956 AN: 151934 Hom.: 1784 Cov.: 31

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

GnomAD3 exomes AF: 0.151 AC: 37943 AN: 250792 Hom.: 3076 AF XY: 0.154 AC XY: 20874 AN XY: 135748

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 SAS exome AF: 0.181

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.: 86 AF XY: 0.157 AC XY: 113951 AN XY: 727206

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.0954

Gnomad4 EAS exome AF: 0.0323

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.144 AC: 21967 AN: 152052 Hom.: 1785 Cov.: 31 AF XY: 0.149 AC XY: 11072 AN XY: 74342

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.0934

Gnomad4 EAS AF: 0.0460

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.124

Alfa AF: 0.141 Hom.: 2274

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:6 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	GeneDx	Mar 30, 2021	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Amyotrophic lateral sclerosis type 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 16, 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

-

- -

Charcot-Marie-Tooth disease axonal type 2CC Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	7.9e-7	P
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Vest4		0.093
MPC		0.11
ClinPred		0.036	T
GERP RS		5.4
gMVP		0.054

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: rs165602; hg19: chr22-29886043; COSMIC: COSV60217077;