Variant chr1-204952115-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001005388.3(NFASC):c.214A>G(p.Ser72Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,456,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NFASC
NM_001005388.3 missense, splice_region

Scores

Splicing: ADA: 0.7137

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFASC. . Gene score misZ 2.5875 (greater than the threshold 3.09). Trascript score misZ 3.5105 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with central and peripheral motor dysfunction.

BP4

Computational evidence support a benign effect (MetaRNN=0.38478357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFASC	NM_001005388.3 linkuse as main transcript	c.214A>G	p.Ser72Gly	missense_variant, splice_region_variant	5/30	ENST00000339876.11	NP_001005388.2
NFASC	NM_001160331.2 linkuse as main transcript	c.196A>G	p.Ser66Gly	missense_variant, splice_region_variant	3/28	ENST00000539706.6	NP_001153803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFASC	ENST00000339876.11 linkuse as main transcript	c.214A>G	p.Ser72Gly	missense_variant, splice_region_variant	5/30	5	NM_001005388.3	ENSP00000344786		O94856-9
NFASC	ENST00000539706.6 linkuse as main transcript	c.196A>G	p.Ser66Gly	missense_variant, splice_region_variant	3/28	5	NM_001160331.2	ENSP00000438614	A2	O94856-11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.0089

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

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

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.040

MetaRNN

Benign

0.38

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

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.9

L;.;.;L;.;L;.;.;.;.

MutationTaster

Benign

0.98

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

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.0

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

REVEL

Benign

0.17

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.019

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

Polyphen

0.96

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

Vest4

0.44

MutPred

0.38

Loss of phosphorylation at S72 (P = 0.1259);.;.;Loss of phosphorylation at S72 (P = 0.1259);.;Loss of phosphorylation at S72 (P = 0.1259);Loss of phosphorylation at S72 (P = 0.1259);.;.;.;

MVP

0.73

MPC

0.51

ClinPred

0.98

GERP RS

4.3

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.71

dbscSNV1_RF

Benign

0.58

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over