1-204944400-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS1

The NM_001005388.3(NFASC):c.85A>G(p.Met29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,361,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

NFASC
NM_001005388.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.64

Publications

1 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09210318).

BP6

Variant 1-204944400-A-G is Benign according to our data. Variant chr1-204944400-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2535566.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000131 (16/1220260) while in subpopulation EAS AF = 0.000715 (13/18180). AF 95% confidence interval is 0.000422. There are 0 homozygotes in GnomAdExome4. There are 11 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFASC	NM_001005388.3 link	c.85A>G	p.Met29Val	missense_variant	Exon 3 of 30	ENST00000339876.11	NP_001005388.2	O94856-9
NFASC	NM_001160331.2 link	c.85A>G	p.Met29Val	missense_variant	Exon 2 of 28	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.85A>G	p.Met29Val	missense_variant	Exon 3 of 30	5	NM_001005388.3	ENSP00000344786.6		O94856-9
NFASC	ENST00000539706.6 link	c.85A>G	p.Met29Val	missense_variant	Exon 2 of 28	5	NM_001160331.2	ENSP00000438614.2		O94856-11

Frequencies

GnomAD3 genomes

AF:

0.00000710

AC:

AN:

140928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000257

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:

0.0000498

AC:

AN:

241080

AF XY:

0.0000764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000677

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1220260

Hom.:

Cov.:

AF XY:

0.0000182

AC XY:

AN XY:

603282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26418

American (AMR)

AF:

0.00

AC:

AN:

35478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17054

East Asian (EAS)

AF:

0.000715

AC:

AN:

18180

South Asian (SAS)

AF:

0.00

AC:

AN:

83416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4382

European-Non Finnish (NFE)

AF:

0.00000209

AC:

AN:

956802

Other (OTH)

AF:

0.0000224

AC:

AN:

44598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000710

AC:

AN:

140928

Hom.:

Cov.:

AF XY:

0.0000147

AC XY:

AN XY:

68192

show subpopulations

African (AFR)

AF:

0.0000257

AC:

AN:

38984

American (AMR)

AF:

0.00

AC:

AN:

14286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3310

East Asian (EAS)

AF:

0.00

AC:

AN:

4054

South Asian (SAS)

AF:

0.00

AC:

AN:

3914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64674

Other (OTH)

AF:

0.00

AC:

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

May 10, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;.;.;.;.;.;.;.;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.056

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.92

D;T;T;D;D;.;D;.;.;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.092

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.34

N;N;N;N;N;N;.;N;N;.

PhyloP100

2.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.95

N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.081

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.040

D;T;T;T;T;D;T;T;T;T

Polyphen

0.0090

B;B;B;B;.;B;.;B;B;.

Vest4

0.45

MutPred

0.24

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;

MVP

0.77

MPC

0.44

ClinPred

0.18

GERP RS

4.2

gMVP

0.36

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

1-204944400-A-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