rs4644268

Variant names:

• chr8-24951612-C-G
• rs4644268
• NM_006158.5:c.*1198G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-24951612-C-G
• chr8-24951612-C-A
• chr8-24951612-C-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.*1198G>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 0.0818 in 152,566 control chromosomes in the GnomAD database, including 682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (682 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (0 hom.)
• Consequence: NEFL NM_006158.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.631
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 8-24951612-C-G is Benign according to our data. Variant chr8-24951612-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 362625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 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.*1198G>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.*1198G>C		3_prime_UTR	Exon 4 of 4	ENSP00000482169.2	P07196
	NEFL	ENST00000916556.1		c.*1198G>C		3_prime_UTR	Exon 4 of 4	ENSP00000586615.1

Frequencies

GnomAD3 genomes AF: 0.0820 AC: 12470 AN: 152068 Hom.: 682 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0798

Gnomad ASJ AF: 0.0828

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0618

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0777

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.00263 AC: 1 AN: 380 Hom.: 0 Cov.: 0 AF XY: 0.00435 AC XY: 1 AN XY: 230

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: 0.00 AC: 0 AN: 374

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: 0.0820 AC: 12475 AN: 152186 Hom.: 682 Cov.: 32 AF XY: 0.0789 AC XY: 5868 AN XY: 74408

African (AFR) AF: 0.118 AC: 4911 AN: 41492

American (AMR) AF: 0.0796 AC: 1216 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0828 AC: 287 AN: 3468

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5172

South Asian (SAS) AF: 0.0622 AC: 300 AN: 4820

European-Finnish (FIN) AF: 0.0173 AC: 184 AN: 10618

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0776 AC: 5281 AN: 68014

Other (OTH) AF: 0.104 AC: 220 AN: 2114

Alfa AF: 0.0257 Hom.: 13

Bravo AF: 0.0889

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease, type I (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.4
DANN	Benign	0.78
PhyloP100		0.63

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: rs4644268; hg19: chr8-24809125;