8-24951655-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006158.5(NEFL):c.*1155T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00809 in 152,698 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (0 hom.)
• Consequence: NEFL NM_006158.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.162

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-24951655-A-C is Benign according to our data. Variant chr8-24951655-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 362626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0081 (1234/152272) while in subpopulation SAS AF= 0.0236 (114/4830). AF 95% confidence interval is 0.0201. There are 10 homozygotes in gnomad4. There are 605 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEFL	NM_006158.5	c.*1155T>G		3_prime_UTR_variant	4/4	ENST00000610854.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFL	ENST00000610854.2	c.*1155T>G		3_prime_UTR_variant	4/4	1	NM_006158.5	P1

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1235 AN: 152154 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00469 AC: 2 AN: 426 Hom.: 0 Cov.: 0 AF XY: 0.00775 AC XY: 2 AN XY: 258

Gnomad4 FIN exome AF: 0.00476

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00810 AC: 1234 AN: 152272 Hom.: 10 Cov.: 32 AF XY: 0.00812 AC XY: 605 AN XY: 74474

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.0283

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0236

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00855 Hom.: 0

Bravo AF: 0.00748

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease, type I Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.4
Dann	Benign	0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs116881703; hg19: chr8-24809168;