chr22-29490054-A-C

Position:

chr22-29490054-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.14 ( 1785 hom., cov: 31)

Exomes 𝑓: 0.16 ( 18654 hom. )

Consequence

NEFH
NM_021076.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 3.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
NEFH	NM_021076.4 linkuse as main transcript	c.2414A>C	p.Glu805Ala	missense_variant	4/4	ENST00000310624.7	NP_066554.2
NEFH	XM_011530200.3 linkuse as main transcript	c.2126A>C	p.Glu709Ala	missense_variant	5/5		XP_011528502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEFH	ENST00000310624.7 linkuse as main transcript	c.2414A>C	p.Glu805Ala	missense_variant	4/4	1	NM_021076.4	ENSP00000311997	P1

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

21956

AN:

151934

Hom.:

1784

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.157

AC XY:

113951

AN XY:

727206

show subpopulations

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.:

AF XY:

0.149

AC XY:

11072

AN XY:

74342

show subpopulations

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:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other: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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.87

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.86

MutationTaster

Benign

7.9e-7

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.38

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Vest4

0.093

MPC

0.11

ClinPred

0.036

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

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