8-24951554-C-T

Variant names:

• chr8-24951554-C-T
• rs2979704
• NM_006158.5:c.*1256G>A

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.*1256G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 152,232 control chromosomes in the GnomAD database, including 47,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47428 hom., cov: 32)
  • Exomes 𝑓: 0.83 (55 hom.)
• Consequence: NEFL NM_006158.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35
• Publications: 11 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=-0.86).
• BP6: Variant 8-24951554-C-T is Benign according to our data. Variant chr8-24951554-C-T is described in ClinVar as Benign. ClinVar VariationId is 362624.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.*1256G>A		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.*1256G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_006158.5	ENSP00000482169.2

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118515 AN: 151946 Hom.: 47400 Cov.: 32

Gnomad AFR AF: 0.601

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.874

Gnomad OTH AF: 0.797

GnomAD4 exome AF: 0.827 AC: 139 AN: 168 Hom.: 55 Cov.: 0 AF XY: 0.836 AC XY: 92 AN XY: 110

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: 0.829 AC: 136 AN: 164

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.780 AC: 118598 AN: 152064 Hom.: 47428 Cov.: 32 AF XY: 0.780 AC XY: 57986 AN XY: 74336

African (AFR) AF: 0.601 AC: 24927 AN: 41452

American (AMR) AF: 0.863 AC: 13198 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 2644 AN: 3468

East Asian (EAS) AF: 0.607 AC: 3126 AN: 5152

South Asian (SAS) AF: 0.827 AC: 3979 AN: 4810

European-Finnish (FIN) AF: 0.826 AC: 8742 AN: 10582

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

European-Non Finnish (NFE) AF: 0.873 AC: 59398 AN: 68002

Other (OTH) AF: 0.795 AC: 1676 AN: 2108

Alfa AF: 0.836 Hom.: 143717

Bravo AF: 0.773

Asia WGS AF: 0.749 AC: 2606 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

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	-0.86
CADD	Benign	7.1
DANN	Benign	0.49
PhyloP100		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2979704; hg19: chr8-24809067; COSMIC: COSV55337552; COSMIC: COSV55337552;