1-204952020-C-T

Position:

• chr1-204952020-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001005388.3(NFASC):​c.119C>T​(p.Pro40Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NFASC NM_001005388.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFASC	NM_001005388.3	c.119C>T	p.Pro40Leu	missense_variant	5/30	ENST00000339876.11	NP_001005388.2
NFASC	NM_001160331.2	c.101C>T	p.Pro34Leu	missense_variant	3/28	ENST00000539706.6	NP_001153803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFASC	ENST00000339876.11	c.119C>T	p.Pro40Leu	missense_variant	5/30	5	NM_001005388.3	ENSP00000344786.6
NFASC	ENST00000539706.6	c.101C>T	p.Pro34Leu	missense_variant	3/28	5	NM_001160331.2	ENSP00000438614.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251256 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461778 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

The c.119C>T (p.P40L) alteration is located in exon 5 (coding exon 3) of the NFASC gene. This alteration results from a C to T substitution at nucleotide position 119, causing the proline (P) at amino acid position 40 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	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;.;D;.;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.69	N;.;.;N;.;N;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.4	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.15	T;T;T;D;T;T;T;T;T;T
Sift4G	Benign	0.090	T;T;T;D;T;T;D;T;T;T
Polyphen		1.0	D;D;D;D;.;D;.;D;D;.
Vest4		0.73
MutPred		0.50		Loss of disorder (P = 0.0135);.;.;Loss of disorder (P = 0.0135);.;Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);.;.;.;
MVP		0.89
MPC		0.85
ClinPred		0.98	D
GERP RS		5.5
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs764209077; hg19: chr1-204921148;