rs57153321

chr8-24953563-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 7.42

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]

ACMG classification

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 GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEFL	NM_006158.5	c.1402G>A	p.Asp468Asn	missense_variant	3/4	ENST00000610854.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFL	ENST00000610854.2	c.1402G>A	p.Asp468Asn	missense_variant	3/4	1	NM_006158.5	P1

Frequencies

GnomAD3 genomes AF: 0.000867 AC: 132 AN: 152206 Hom.: 0 Cov.: 33

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.: 3 AF XY: 0.00150 AC XY: 202 AN XY: 135100

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.: 5 Cov.: 32 AF XY: 0.00147 AC XY: 1070 AN XY: 727098

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.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74494

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.: 0

Bravo AF: 0.000839

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.00181 AC: 15

ExAC AF: 0.00134 AC: 162

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2019	This variant is associated with the following publications: (PMID: 12566280, 22765307, 17052987) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	NEFL: BP4, BS1:Supporting -

not specified Benign:1

Likely benign, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2020

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Benign	0.90
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0078	T
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.38	T
Polyphen		0.037	B
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

Other links and lift over

dbSNP: rs57153321; hg19: chr8-24811077;