rs377121179

Variant names:

• chr8-24952832-T-C
• rs377121179
• NM_006158.5:c.1610A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_006158.5(NEFL):​c.1610A>G​(p.Gln537Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000826 in 1,613,712 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q537Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (1 hom.)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.707
• Publications: 5 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 -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 0.63774 (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease type 1F, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease type 2B5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.035324752).
• BP6: Variant 8-24952832-T-C is Benign according to our data. Variant chr8-24952832-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220209.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000538 (82/152334) while in subpopulation NFE AF = 0.000926 (63/68028). AF 95% confidence interval is 0.000742. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1610A>G	p.Gln537Arg	missense	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.1610A>G	p.Gln537Arg	missense	Exon 4 of 4	ENSP00000482169.2	P07196
	NEFL	ENST00000916556.1		c.1598A>G	p.Gln533Arg	missense	Exon 4 of 4	ENSP00000586615.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000433 AC: 108 AN: 249264 AF XY: 0.000422

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000646

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.000856 AC: 1251 AN: 1461378 Hom.: 1 Cov.: 30 AF XY: 0.000840 AC XY: 611 AN XY: 726990

African (AFR) AF: 0.000149 AC: 5 AN: 33474

American (AMR) AF: 0.000827 AC: 37 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53384

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

European-Non Finnish (NFE) AF: 0.000998 AC: 1109 AN: 1111610

Other (OTH) AF: 0.00159 AC: 96 AN: 60356

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74490

African (AFR) AF: 0.000144 AC: 6 AN: 41574

American (AMR) AF: 0.000784 AC: 12 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000655 Hom.: 0

Bravo AF: 0.000540

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000527 AC: 2

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.000347 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Charcot-Marie-Tooth disease type 1F;C1843225:Charcot-Marie-Tooth disease type 2E;C4693509:Charcot-Marie-Tooth disease, dominant intermediate G (1)
-	-	1	Charcot-Marie-Tooth disease type 2E (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.035	T
PhyloP100		0.71
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.054
MVP		0.71
GERP RS		3.5
Varity_R		0.082
gMVP		0.0039

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: rs377121179; hg19: chr8-24810345;