8-24953563-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006158.5(NEFL):c.1402G>A(p.Asp468Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,980 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 5 hom. )

Consequence

NEFL
NM_006158.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 7.42

Variant links:

Genes affected

NEFL (HGNC:7739): (neurofilament light chain) Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and they functionally maintain the neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the light chain neurofilament protein. Mutations in this gene cause Charcot-Marie-Tooth disease types 1F (CMT1F) and 2E (CMT2E), disorders of the peripheral nervous system that are characterized by distinct neuropathies. A pseudogene has been identified on chromosome Y. [provided by RefSeq, Oct 2008]

NEFL links:

MIR6841 (HGNC:50070): (microRNA 6841) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6841 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=0.007828772).

BP6

Variant 8-24953563-C-T is Benign according to our data. Variant chr8-24953563-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 66676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-24953563-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000867 (132/152324) while in subpopulation SAS AF= 0.00248 (12/4830). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFL	NM_006158.5 link	c.1402G>A	p.Asp468Asn	missense_variant	Exon 3 of 4	ENST00000610854.2	NP_006149.2	P07196
MIR6841	NR_106900.1 link	n.*233G>A		downstream_gene_variant
MIR6841	unassigned_transcript_1462	n.*233G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEFL	ENST00000610854.2 link	c.1402G>A	p.Asp468Asn	missense_variant	Exon 3 of 4	1	NM_006158.5	ENSP00000482169.2		P07196
MIR6841	ENST00000637129.1 link	n.*233G>A		downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.000867

AC:

132

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00130

AC:

323

AN:

248962

Hom.:

AF XY:

0.00150

AC XY:

202

AN XY:

135100

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00358

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00281

Gnomad FIN exome

AF:

0.000604

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.00232

GnomAD4 exome

AF:

0.00146

AC:

2129

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1070

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00341

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00290

Gnomad4 FIN exome

AF:

0.000506

Gnomad4 NFE exome

AF:

0.00147

Gnomad4 OTH exome

AF:

0.00154

GnomAD4 genome

AF:

0.000867

AC:

132

AN:

152324

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00148

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000255

AC:

ESP6500EA

AF:

0.00181

AC:

ExAC

AF:

0.00134

AC:

162

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEFL: BP4, BS1:Supporting -

Jan 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12566280, 22765307, 17052987) -

not specified

Benign:1

Inherited Neuropathy Consortium

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 10, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease type 1F

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2E

Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0078

PrimateAI

Benign

0.45

Sift4G

Benign

0.38

Polyphen

0.037

Vest4

0.24

MVP

0.63

GERP RS

5.9

Varity_R

0.18

gMVP

0.19

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