1-204954297-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001005388.3(NFASC):c.325C>A(p.Pro109Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NFASC NM_001005388.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NFASC
• BP4: Computational evidence support a benign effect (MetaRNN=0.27047592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFASC	NM_001005388.3	c.325C>A	p.Pro109Thr	missense_variant	6/30	ENST00000339876.11
NFASC	NM_001160331.2	c.307C>A	p.Pro103Thr	missense_variant	4/28	ENST00000539706.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFASC	ENST00000339876.11	c.325C>A	p.Pro109Thr	missense_variant	6/30	5	NM_001005388.3
NFASC	ENST00000539706.6	c.307C>A	p.Pro103Thr	missense_variant	4/28	5	NM_001160331.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251104 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135768

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727218

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Feb 15, 2023

The c.325C>A (p.P109T) alteration is located in exon 6 (coding exon 4) of the NFASC gene. This alteration results from a C to A substitution at nucleotide position 325, causing the proline (P) at amino acid position 109 to be replaced by a threonine (T). 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	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;.;D;.;.;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.35	N;.;.;N;.;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	N;N;N;D;N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.23	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.066	T;T;T;T;T;T;T;T;T;T
Polyphen		0.30	B;B;D;D;.;B;.;B;D;.
Vest4		0.75
MutPred		0.28		Gain of phosphorylation at P109 (P = 0.0233);.;.;Gain of phosphorylation at P109 (P = 0.0233);.;Gain of phosphorylation at P109 (P = 0.0233);Gain of phosphorylation at P109 (P = 0.0233);.;.;.;
MVP		0.70
MPC		1.2
ClinPred		0.86	D
GERP RS		5.4
gMVP		0.58

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

Other links and lift over

dbSNP: rs780974163; hg19: chr1-204923425;