rs1059111

Variant names:

• chr8-24952575-T-A
• rs1059111
• NM_006158.5:c.*235A>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 2.92
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 1F

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease type 2E

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 2B5

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
NEFL	NM_006158.5	c.*235A>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000610854.2	NP_006149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEFL	ENST00000610854.2	c.*235A>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_006158.5	ENSP00000482169.2

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

African (AFR) AF: 0.600 AC: 7173 AN: 11948

American (AMR) AF: 0.880 AC: 14060 AN: 15984

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 9782 AN: 12668

East Asian (EAS) AF: 0.629 AC: 18016 AN: 28640

South Asian (SAS) AF: 0.841 AC: 30401 AN: 36158

European-Finnish (FIN) AF: 0.840 AC: 23044 AN: 27422

Middle Eastern (MID) AF: 0.791 AC: 1451 AN: 1834

European-Non Finnish (NFE) AF: 0.876 AC: 226412 AN: 258532

Other (OTH) AF: 0.829 AC: 20057 AN: 24180

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

African (AFR) AF: 0.603 AC: 24978 AN: 41448

American (AMR) AF: 0.863 AC: 13203 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2646 AN: 3470

East Asian (EAS) AF: 0.607 AC: 3131 AN: 5162

South Asian (SAS) AF: 0.827 AC: 3983 AN: 4818

European-Finnish (FIN) AF: 0.826 AC: 8730 AN: 10568

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.874 AC: 59424 AN: 68024

Other (OTH) AF: 0.794 AC: 1677 AN: 2112

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		2.9

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

Other links and lift over

dbSNP: rs1059111; hg19: chr8-24810088;