rs60261494

Positions:

• chr8-24956493-GG-CT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_006158.5(NEFL):​c.22_23delinsAG​(p.Pro8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P8T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:2
• Conservation: PhyloP100: 2.76

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Head (size 90) in uniprot entity NFL_HUMAN there are 25 pathogenic changes around while only 5 benign (83%) in NM_006158.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-24956493-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 8-24956493-GG-CT is Pathogenic according to our data. Variant chr8-24956493-GG-CT is described in ClinVar as [Pathogenic]. Clinvar id is 14030.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEFL	NM_006158.5	c.22_23delinsAG	p.Pro8Arg	missense_variant	1/4	ENST00000610854.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFL	ENST00000610854.2	c.22_23delinsAG	p.Pro8Arg	missense_variant	1/4	1	NM_006158.5	P1
	ENST00000607735.2	n.553_554delinsCT		non_coding_transcript_exon_variant	1/1
NEFL	ENST00000615973.1	n.228_229delinsAG		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease type 2E Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2007	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

Charcot-Marie-Tooth disease type 1F Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 2007

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs60261494; hg19: chr8-24814007;