chr22-29480283-G-A

Position:

• chr22-29480283-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021076.4(NEFH):​c.21G>A​(p.Ala7=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,509,734 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (32 hom.)
• Consequence: NEFH NM_021076.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.52

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 22-29480283-G-A is Benign according to our data. Variant chr22-29480283-G-A is described in ClinVar as [Benign]. Clinvar id is 774538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-29480283-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00544 (828/152326) while in subpopulation AMR AF= 0.0155 (237/15304). AF 95% confidence interval is 0.0139. There are 10 homozygotes in gnomad4. There are 408 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 828 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEFH	NM_021076.4	c.21G>A	p.Ala7=	synonymous_variant	1/4	ENST00000310624.7	NP_066554.2
NEFH	XM_011530200.3	c.21G>A	p.Ala7=	synonymous_variant	1/5		XP_011528502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEFH	ENST00000310624.7	c.21G>A	p.Ala7=	synonymous_variant	1/4	1	NM_021076.4	ENSP00000311997	P1
	ENST00000634116.1	n.321-41C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 827 AN: 152218 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.00587

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00565 AC: 588 AN: 103996 Hom.: 4 AF XY: 0.00554 AC XY: 323 AN XY: 58324

Gnomad AFR exome AF: 0.000991

Gnomad AMR exome AF: 0.00978

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.00224

Gnomad FIN exome AF: 0.000782

Gnomad NFE exome AF: 0.00610

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00501 AC: 6794 AN: 1357408 Hom.: 32 Cov.: 33 AF XY: 0.00499 AC XY: 3340 AN XY: 669828

Gnomad4 AFR exome AF: 0.000901

Gnomad4 AMR exome AF: 0.00948

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.00111

Gnomad4 NFE exome AF: 0.00513

Gnomad4 OTH exome AF: 0.00763

GnomAD4 genome AF: 0.00544 AC: 828 AN: 152326 Hom.: 10 Cov.: 32 AF XY: 0.00548 AC XY: 408 AN XY: 74478

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00587

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00338 Hom.: 3

Bravo AF: 0.00580

Asia WGS AF: 0.00173 AC: 6 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	NEFH: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs192350983; hg19: chr22-29876272;