rs947517631

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001005388.3(NFASC):c.263C>T(p.Pro88Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

NFASC
NM_001005388.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.78

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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFASC	NM_001005388.3 link	c.263C>T	p.Pro88Leu	missense_variant	Exon 6 of 30	ENST00000339876.11	NP_001005388.2	O94856-9
NFASC	NM_001160331.2 link	c.245C>T	p.Pro82Leu	missense_variant	Exon 4 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.263C>T	p.Pro88Leu	missense_variant	Exon 6 of 30	5	NM_001005388.3	ENSP00000344786.6		O94856-9
NFASC	ENST00000539706.6 link	c.245C>T	p.Pro82Leu	missense_variant	Exon 4 of 28	5	NM_001160331.2	ENSP00000438614.2		O94856-11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 01, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.263C>T (p.P88L) alteration is located in exon 6 (coding exon 4) of the NFASC gene. This alteration results from a C to T substitution at nucleotide position 263, causing the proline (P) at amino acid position 88 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

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

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D;D;D;.;D;.;.;D

M_CAP

Benign

0.073

MetaRNN

Pathogenic

0.78

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

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.3

M;.;.;M;.;M;.;.;.;.

PhyloP100

4.8

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.0

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

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.93

P;P;P;D;.;P;.;P;P;.

Vest4

0.79

MutPred

0.54

Loss of disorder (P = 0.0183);.;.;Loss of disorder (P = 0.0183);.;Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);.;.;.;

MVP

0.81

MPC

1.1

ClinPred

0.99

GERP RS

5.4

gMVP

0.62

Mutation Taster

=20/80

disease causing

(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

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rs947517631

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