1-204952057-C-G

Variant names:

• chr1-204952057-C-G
• NM_001005388.3:c.156C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001005388.3(NFASC):​c.156C>G​(p.Ile52Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I52V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFASC NM_001005388.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.444
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFASC	NM_001005388.3	c.156C>G	p.Ile52Met	missense_variant	Exon 5 of 30	ENST00000339876.11	NP_001005388.2
NFASC	NM_001160331.2	c.138C>G	p.Ile46Met	missense_variant	Exon 3 of 28	ENST00000539706.6	NP_001153803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFASC	ENST00000339876.11	c.156C>G	p.Ile52Met	missense_variant	Exon 5 of 30	5	NM_001005388.3	ENSP00000344786.6
NFASC	ENST00000539706.6	c.138C>G	p.Ile46Met	missense_variant	Exon 3 of 28	5	NM_001160331.2	ENSP00000438614.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.156C>G (p.I52M) alteration is located in exon 5 (coding exon 3) of the NFASC gene. This alteration results from a C to G substitution at nucleotide position 156, causing the isoleucine (I) at amino acid position 52 to be replaced by a methionine (M). 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	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;.;.;.;.;.;.;.;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;.;D;.;.;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.8	M;.;.;M;.;M;.;.;.;.
PhyloP100		0.44
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;.;D;.;D;D;.
Vest4		0.83
MutPred		0.45		Gain of disorder (P = 0.0606);.;.;Gain of disorder (P = 0.0606);.;Gain of disorder (P = 0.0606);Gain of disorder (P = 0.0606);.;.;.;
MVP		0.79
MPC		1.2
ClinPred		0.99	D
GERP RS		2.6
gMVP		0.63
Mutation Taster		=27/73	disease causing

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

Other links and lift over

hg19: chr1-204921185;