8-24951927-C-G

Variant names:

• chr8-24951927-C-G
• rs76387248
• NM_006158.5:c.*883G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006158.5(NEFL):​c.*883G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 152,450 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (0 hom.)
• Consequence: NEFL NM_006158.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.411
• Publications: 2 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: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-24951927-C-G is Benign according to our data. Variant chr8-24951927-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 362629.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006158.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFL	NM_006158.5	MANE Select	c.*883G>C		3_prime_UTR	Exon 4 of 4	NP_006149.2	P07196

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFL	ENST00000610854.2	TSL:1 MANE Select	c.*883G>C		3_prime_UTR	Exon 4 of 4	ENSP00000482169.2	P07196
	NEFL	ENST00000916556.1		c.*883G>C		3_prime_UTR	Exon 4 of 4	ENSP00000586615.1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2683 AN: 152116 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.0328

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00637

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00463 AC: 1 AN: 216 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 138

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00476 AC: 1 AN: 210

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0177 AC: 2696 AN: 152234 Hom.: 35 Cov.: 32 AF XY: 0.0180 AC XY: 1343 AN XY: 74426

African (AFR) AF: 0.0356 AC: 1480 AN: 41532

American (AMR) AF: 0.00791 AC: 121 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.0592 AC: 307 AN: 5182

South Asian (SAS) AF: 0.0324 AC: 156 AN: 4812

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00637 AC: 433 AN: 68012

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0103 Hom.: 2

Bravo AF: 0.0188

Asia WGS AF: 0.0530 AC: 184 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.52
PhyloP100		-0.41

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: rs76387248; hg19: chr8-24809440;