ENST00000607735.3:n.1199T>C

Variant names:

• chr8-24956889-T-C
• rs2979687
• ENST00000607735.3:n.1199T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000607735.3(ENSG00000272157):​n.1199T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 322,422 control chromosomes in the GnomAD database, including 64,100 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.60 (27762 hom., cov: 29)
  • Exomes 𝑓: 0.65 (36338 hom.)
• Consequence: ENSG00000272157 ENST00000607735.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.84
• Publications: 7 publications found

Genes affected

ENSG00000272157 (HGNC:):

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: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000272157	ENST00000607735.3	n.1199T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
NEFL	ENST00000615973.1	n.-168A>G		upstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90182 AN: 151454 Hom.: 27741 Cov.: 29

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.585

GnomAD4 exome AF: 0.650 AC: 111127 AN: 170848 Hom.: 36338 Cov.: 0 AF XY: 0.651 AC XY: 58857 AN XY: 90408

African (AFR) AF: 0.421 AC: 2300 AN: 5462

American (AMR) AF: 0.715 AC: 5369 AN: 7512

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2622 AN: 4542

East Asian (EAS) AF: 0.588 AC: 4595 AN: 7810

South Asian (SAS) AF: 0.667 AC: 17416 AN: 26124

European-Finnish (FIN) AF: 0.632 AC: 4621 AN: 7310

Middle Eastern (MID) AF: 0.527 AC: 351 AN: 666

European-Non Finnish (NFE) AF: 0.666 AC: 68100 AN: 102238

Other (OTH) AF: 0.626 AC: 5753 AN: 9184

GnomAD4 genome AF: 0.595 AC: 90262 AN: 151574 Hom.: 27762 Cov.: 29 AF XY: 0.598 AC XY: 44262 AN XY: 74040

African (AFR) AF: 0.437 AC: 18047 AN: 41288

American (AMR) AF: 0.689 AC: 10489 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1987 AN: 3460

East Asian (EAS) AF: 0.585 AC: 2973 AN: 5082

South Asian (SAS) AF: 0.679 AC: 3256 AN: 4792

European-Finnish (FIN) AF: 0.621 AC: 6534 AN: 10526

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45036 AN: 67876

Other (OTH) AF: 0.585 AC: 1236 AN: 2112

Alfa AF: 0.593 Hom.: 4615

Bravo AF: 0.594

Asia WGS AF: 0.659 AC: 2292 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.057
DANN	Benign	0.43
PhyloP100		-5.8
PromoterAI		-0.027	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2979687; hg19: chr8-24814403;