rs1059111

Positions:

• chr8-24952575-T-A
• chr8-24952575-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_006158.5(NEFL):​c.*235A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.824 in 569,468 control chromosomes in the GnomAD database, including 196,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47468 hom., cov: 32)
  • Exomes 𝑓: 0.84 (148583 hom.)
• Consequence: NEFL NM_006158.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.92

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 8-24952575-T-A is Benign according to our data. Variant chr8-24952575-T-A is described in ClinVar as [Benign]. Clinvar id is 362641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEFL	NM_006158.5	c.*235A>T		3_prime_UTR_variant	4/4	ENST00000610854.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFL	ENST00000610854.2	c.*235A>T		3_prime_UTR_variant	4/4	1	NM_006158.5	P1

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118597 AN: 151984 Hom.: 47440 Cov.: 32

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.874

Gnomad OTH AF: 0.796

GnomAD4 exome AF: 0.840 AC: 350396 AN: 417366 Hom.: 148583 Cov.: 5 AF XY: 0.841 AC XY: 183452 AN XY: 218222

Gnomad4 AFR exome AF: 0.600

Gnomad4 AMR exome AF: 0.880

Gnomad4 ASJ exome AF: 0.772

Gnomad4 EAS exome AF: 0.629

Gnomad4 SAS exome AF: 0.841

Gnomad4 FIN exome AF: 0.840

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.829

GnomAD4 genome AF: 0.780 AC: 118683 AN: 152102 Hom.: 47468 Cov.: 32 AF XY: 0.780 AC XY: 58020 AN XY: 74362

Gnomad4 AFR AF: 0.603

Gnomad4 AMR AF: 0.863

Gnomad4 ASJ AF: 0.763

Gnomad4 EAS AF: 0.607

Gnomad4 SAS AF: 0.827

Gnomad4 FIN AF: 0.826

Gnomad4 NFE AF: 0.874

Gnomad4 OTH AF: 0.794

Alfa AF: 0.803 Hom.: 2698

Bravo AF: 0.774

Asia WGS AF: 0.751 AC: 2610 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is associated with the following publications: (PMID: 25312269) -

Charcot-Marie-Tooth disease, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.87

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: rs1059111; hg19: chr8-24810088;