chr1-204954942-A-G

Position:

• chr1-204954942-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001005388.3(NFASC):​c.526A>G​(p.Met176Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 9.30

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 5 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFASC	NM_001005388.3	c.526A>G	p.Met176Val	missense_variant	7/30	ENST00000339876.11
NFASC	NM_001160331.2	c.508A>G	p.Met170Val	missense_variant	5/28	ENST00000539706.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFASC	ENST00000339876.11	c.526A>G	p.Met176Val	missense_variant	7/30	5	NM_001005388.3
NFASC	ENST00000539706.6	c.508A>G	p.Met170Val	missense_variant	5/28	5	NM_001160331.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with central and peripheral motor dysfunction Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.526A>G p.Met176Val variant in NFASC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Met176Val variant is novel not in any individuals in both gnomAD Exomes and 1000 Genomes databases. This variant has not been reported to the ClinVar database. The amino acid change p.Met176Val in NFASC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 176 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;.;.;.;.;.;.;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;.;.;.;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D;D;.
Vest4		0.80
MutPred		0.37		Gain of catalytic residue at M176 (P = 0.0075);.;.;Gain of catalytic residue at M176 (P = 0.0075);.;Gain of catalytic residue at M176 (P = 0.0075);.;.;.;
MVP		0.79
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-204924070;