Genetic Variant NM_001005388.3:c.-91+5855A>G (chr1-204926595-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001005388.3(NFASC):c.-91+5855A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000334 in 149,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 29)

Consequence

NFASC
NM_001005388.3 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.08

Publications

0 publications found

Variant links:

Genes affected

NFASC (HGNC:29866): (neurofascin) This gene encodes an L1 family immunoglobulin cell adhesion molecule with multiple IGcam and fibronectin domains. The protein functions in neurite outgrowth, neurite fasciculation, and organization of the axon initial segment (AIS) and nodes of Ranvier on axons during early development. Both the AIS and nodes of Ranvier contain high densities of voltage-gated Na+ (Nav) channels which are clustered by interactions with cytoskeletal and scaffolding proteins including this protein, gliomedin, ankyrin 3 (ankyrin-G), and betaIV spectrin. This protein links the AIS extracellular matrix to the intracellular cytoskeleton. This gene undergoes extensive alternative splicing, and the full-length nature of some variants has not been determined.[provided by RefSeq, May 2009]

NFASC Gene-Disease associations (from GenCC):

neurodevelopmental disorder with central and peripheral motor dysfunction
Inheritance: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

NFASC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.03).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFASC	NM_001005388.3 link	c.-91+5855A>G		intron_variant	Intron 2 of 29	ENST00000339876.11	NP_001005388.2	O94856-9
NFASC	NM_001160331.2 link	c.-90-17631A>G		intron_variant	Intron 1 of 27	ENST00000539706.6	NP_001153803.1	O94856-11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFASC	ENST00000339876.11 link	c.-91+5855A>G		intron_variant	Intron 2 of 29	5	NM_001005388.3	ENSP00000344786.6		O94856-9
NFASC	ENST00000539706.6 link	c.-90-17631A>G		intron_variant	Intron 1 of 27	5	NM_001160331.2	ENSP00000438614.2		O94856-11

Frequencies

GnomAD3 genomes

AF:

0.0000334

AC:

AN:

149498

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000123

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

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

GnomAD4 genome

AF:

0.0000334

AC:

AN:

149498

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72902

show subpopulations

African (AFR)

AF:

0.000123

AC:

AN:

40684

American (AMR)

AF:

0.00

AC:

AN:

14960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5036

South Asian (SAS)

AF:

0.00

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67484

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with central and peripheral motor dysfunction

Uncertain:1

May 14, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.3

(source)

DANN

Benign

0.59

PhyloP100

-1.1

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

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NM_001005388.3:c.-91+5855A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over