dbSNP rs267607535: NEFH:p.Ala686_Lys699del (chr22-29489620-CAAGTCCCCTGAGAAGGCCAAGTCCCCAGTGAAGGCAGAAGCA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_021076.4(NEFH):c.2057_2098delCAGAAGCAAAGTCCCCTGAGAAGGCCAAGTCCCCAGTGAAGG(p.Ala686_Lys699del) variant causes a disruptive inframe deletion change. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Failed GnomAD Quality Control

Consequence

NEFH
NM_021076.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

risk factor no assertion criteria provided O:2

Conservation

PhyloP100: 4.71

Publications

0 publications found

Variant links:

Genes affected

NEFH (HGNC:7737): (neurofilament heavy chain) Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and functionally maintain neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the heavy neurofilament protein. This protein is commonly used as a biomarker of neuronal damage and susceptibility to amyotrophic lateral sclerosis (ALS) has been associated with mutations in this gene. [provided by RefSeq, Oct 2008]

NEFH Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2CC
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NEFH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021076.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFH	NM_021076.4 link	c.2057_2098delCAGAAGCAAAGTCCCCTGAGAAGGCCAAGTCCCCAGTGAAGG	p.Ala686_Lys699del	disruptive_inframe_deletion	Exon 4 of 4	ENST00000310624.7	NP_066554.2	P12036
NEFH	XM_011530200.3 link	c.1769_1810delCAGAAGCAAAGTCCCCTGAGAAGGCCAAGTCCCCAGTGAAGG	p.Ala590_Lys603del	disruptive_inframe_deletion	Exon 5 of 5		XP_011528502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEFH	ENST00000310624.7 link	c.2057_2098delCAGAAGCAAAGTCCCCTGAGAAGGCCAAGTCCCCAGTGAAGG	p.Ala686_Lys699del	disruptive_inframe_deletion	Exon 4 of 4	1	NM_021076.4	ENSP00000311997.6		P12036

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

141912

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

251064

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

142018

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69306

African (AFR)

AF:

0.00

AC:

AN:

38052

American (AMR)

AF:

0.00

AC:

AN:

14348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3366

East Asian (EAS)

AF:

0.00

AC:

AN:

4742

South Asian (SAS)

AF:

0.00

AC:

AN:

4346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64612

Other (OTH)

AF:

0.00

AC:

AN:

1988

ClinVar

Significance: risk factor

Submissions summary: Other:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis, susceptibility to

Other:1

Feb 01, 1999

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.7

Mutation Taster

=50/150

disease causing (long InDel)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over