22-29480323-G-A

Position:

• chr22-29480323-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_021076.4(NEFH):​c.61G>A​(p.Gly21Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,355,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NEFH NM_021076.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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]

ENSG00000282816 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37593138).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEFH	NM_021076.4	c.61G>A	p.Gly21Ser	missense_variant	1/4	ENST00000310624.7	NP_066554.2
NEFH	XM_011530200.3	c.61G>A	p.Gly21Ser	missense_variant	1/5		XP_011528502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEFH	ENST00000310624.7	c.61G>A	p.Gly21Ser	missense_variant	1/4	1	NM_021076.4	ENSP00000311997.6
ENSG00000282816	ENST00000634116.1	n.321-81C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000140 AC: 19 AN: 1355126 Hom.: 0 Cov.: 33 AF XY: 0.0000120 AC XY: 8 AN XY: 668712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.0000885

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 21 of the NEFH protein (p.Gly21Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEFH-related conditions. ClinVar contains an entry for this variant (Variation ID: 1912641). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NEFH protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.73	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.43	T
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.14
Sift	Benign	0.080	T
Sift4G	Pathogenic	0.0	D
Vest4		0.29
MutPred		0.33		Gain of glycosylation at G21 (P = 0.0072);
MVP		0.69
MPC		1.1
ClinPred		0.37	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
gMVP		0.48

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: rs1013169782; hg19: chr22-29876312;