chr1-204954283-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001005388.3(NFASC):​c.311G>A​(p.Arg104His) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

NFASC
NM_001005388.3 missense

Scores

5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.26
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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=0.21975318).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NFASCNM_001005388.3 linkuse as main transcriptc.311G>A p.Arg104His missense_variant 6/30 ENST00000339876.11
NFASCNM_001160331.2 linkuse as main transcriptc.293G>A p.Arg98His missense_variant 4/28 ENST00000539706.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NFASCENST00000339876.11 linkuse as main transcriptc.311G>A p.Arg104His missense_variant 6/305 NM_001005388.3 O94856-9
NFASCENST00000539706.6 linkuse as main transcriptc.293G>A p.Arg98His missense_variant 4/285 NM_001160331.2 A2O94856-11

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251372
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461878
Hom.:
0
Cov.:
32
AF XY:
0.0000220
AC XY:
16
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 30, 2023The c.311G>A (p.R104H) alteration is located in exon 6 (coding exon 4) of the NFASC gene. This alteration results from a G to A substitution at nucleotide position 311, causing the arginine (R) at amino acid position 104 to be replaced by a histidine (H). 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
Benign
-0.027
T
BayesDel_noAF
Uncertain
-0.040
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.10
.;.;.;.;.;.;.;.;.;T
Eigen
Benign
-0.088
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;.;D;.;.;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.22
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.037
D
MutationAssessor
Benign
0.39
N;.;.;N;.;N;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.77
N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.12
Sift
Benign
0.15
T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.60
T;T;T;T;T;T;T;T;T;T
Polyphen
0.027
B;B;B;B;.;B;.;B;B;.
Vest4
0.34
MutPred
0.52
Loss of MoRF binding (P = 0.0325);.;.;Loss of MoRF binding (P = 0.0325);.;Loss of MoRF binding (P = 0.0325);Loss of MoRF binding (P = 0.0325);.;.;.;
MVP
0.82
MPC
0.47
ClinPred
0.25
T
GERP RS
5.4
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759862571; hg19: chr1-204923411; API