rs185200977

chr8-24955932-G-Achr8-24955932-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006158.5(NEFL):c.584C>T(p.Ala195Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00048 in 1,603,858 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.35

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009539366).
• BP6: Variant 8-24955932-G-A is Benign according to our data. Variant chr8-24955932-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 386660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00249 (379/152320) while in subpopulation AFR AF= 0.00808 (336/41586). AF 95% confidence interval is 0.00737. There are 3 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEFL	NM_006158.5	c.584C>T	p.Ala195Val	missense_variant	1/4	ENST00000610854.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFL	ENST00000610854.2	c.584C>T	p.Ala195Val	missense_variant	1/4	1	NM_006158.5	P1
NEFL	ENST00000615973.1	n.790C>T		non_coding_transcript_exon_variant	1/1
	ENST00000607735.2			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152202 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00813

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000602 AC: 142 AN: 235930 Hom.: 2 AF XY: 0.000463 AC XY: 60 AN XY: 129700

Gnomad AFR exome AF: 0.00771

Gnomad AMR exome AF: 0.000554

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000923

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000269 AC: 391 AN: 1451538 Hom.: 2 Cov.: 36 AF XY: 0.000249 AC XY: 180 AN XY: 722618

Gnomad4 AFR exome AF: 0.00801

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152320 Hom.: 3 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74482

Gnomad4 AFR AF: 0.00808

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.00303

ESP6500AA AF: 0.00784 AC: 30

ESP6500EA AF: 0.000488 AC: 4

ExAC AF: 0.000781 AC: 94

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 31, 2017

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	30
Dann	Benign	0.97
DEOGEN2	Uncertain	0.54	D;.;T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0095	T;T;T
PrimateAI	Uncertain	0.58	T
Sift4G	Benign	0.56	T;.;T
Polyphen		0.18	B;.;.
Vest4		0.084
MVP		0.79
GERP RS		5.8
Varity_R		0.20
gMVP		0.33

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: rs185200977; hg19: chr8-24813446;