Variant 22-29480283-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.52

Variant links:

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

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	UniProt
NEFH	NM_021076.4 linkuse as main transcript	c.21G>A	p.Ala7=	synonymous_variant	1/4	ENST00000310624.7
NEFH	XM_011530200.3 linkuse as main transcript	c.21G>A	p.Ala7=	synonymous_variant	1/5

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00543

AC:

827

AN:

152218

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00554

AC XY:

323

AN XY:

58324

show subpopulations

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.:

Cov.:

AF XY:

0.00499

AC XY:

3340

AN XY:

669828

show subpopulations

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.:

Cov.:

AF XY:

0.00548

AC XY:

408

AN XY:

74478

show subpopulations

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.:

Bravo

AF:

0.00580

Asia WGS

AF:

0.00173

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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	clinical testing	GeneDx	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over