rs759524661

Variant names:

• chr8-24955532-C-A
• rs759524661
• NM_006158.5:c.984G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-24955532-C-A
• chr8-24955532-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_006158.5(NEFL):​c.984G>T​(p.Ala328Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: NEFL NM_006158.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.312
• Publications: 0 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

ENSG00000272157 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 8-24955532-C-A is Benign according to our data. Variant chr8-24955532-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 417204.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.312 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFL	NM_006158.5	c.984G>T	p.Ala328Ala	synonymous_variant	Exon 1 of 4	ENST00000610854.2	NP_006149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEFL	ENST00000610854.2	c.984G>T	p.Ala328Ala	synonymous_variant	Exon 1 of 4	1	NM_006158.5	ENSP00000482169.2
NEFL	ENST00000615973.1	n.1190G>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000272157	ENST00000607735.3	n.-159C>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248960 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461192 Hom.: 0 Cov.: 36 AF XY: 0.0000151 AC XY: 11 AN XY: 726882

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111840

Other (OTH) AF: 0.0000331 AC: 2 AN: 60368

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2E Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		-0.31

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: rs759524661; hg19: chr8-24813046;