rs3761

Variant names:

• chr8-24951703-G-A
• rs3761
• NM_006158.5:c.*1107C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006158.5(NEFL):​c.*1107C>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 0.102 in 152,636 control chromosomes in the GnomAD database, including 968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (965 hom., cov: 33)
  • Exomes 𝑓: 0.17 (3 hom.)
• Consequence: NEFL NM_006158.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.516
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-24951703-G-A is Benign according to our data. Variant chr8-24951703-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 362627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFL	NM_006158.5	c.*1107C>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.*1107C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_006158.5	ENSP00000482169.2

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15561 AN: 152088 Hom.: 966 Cov.: 33

Gnomad AFR AF: 0.0461

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0939

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0214

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.174 AC: 75 AN: 430 Hom.: 3 Cov.: 0 AF XY: 0.192 AC XY: 50 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.175 AC: 74 AN: 424

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.102 AC: 15559 AN: 152206 Hom.: 965 Cov.: 33 AF XY: 0.103 AC XY: 7652 AN XY: 74410

African (AFR) AF: 0.0461 AC: 1915 AN: 41552

American (AMR) AF: 0.0938 AC: 1434 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3466

East Asian (EAS) AF: 0.0210 AC: 109 AN: 5180

South Asian (SAS) AF: 0.0854 AC: 412 AN: 4824

European-Finnish (FIN) AF: 0.187 AC: 1984 AN: 10586

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.132 AC: 8967 AN: 67992

Other (OTH) AF: 0.103 AC: 218 AN: 2114

Alfa AF: 0.124 Hom.: 275

Bravo AF: 0.0907

Asia WGS AF: 0.0630 AC: 219 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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: Likely 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	-0.81
CADD	Benign	3.8
DANN	Benign	0.59
PhyloP100		0.52

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: rs3761; hg19: chr8-24809216;