chr1-204952071-A-G

Position:

• chr1-204952071-A-G

Variant summary

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

The NM_001005388.3(NFASC):​c.170A>G​(p.Asp57Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 9.24

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 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, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFASC	NM_001005388.3	c.170A>G	p.Asp57Gly	missense_variant	5/30	ENST00000339876.11
NFASC	NM_001160331.2	c.152A>G	p.Asp51Gly	missense_variant	3/28	ENST00000539706.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFASC	ENST00000339876.11	c.170A>G	p.Asp57Gly	missense_variant	5/30	5	NM_001005388.3
NFASC	ENST00000539706.6	c.152A>G	p.Asp51Gly	missense_variant	3/28	5	NM_001160331.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251410 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135882

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

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

Mar 19, 2024

The c.170A>G (p.D57G) alteration is located in exon 5 (coding exon 3) of the NFASC gene. This alteration results from a A to G substitution at nucleotide position 170, causing the aspartic acid (D) at amino acid position 57 to be replaced by a glycine (G). 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	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	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	Benign	-0.74	T
MutationAssessor	Benign	0.92	L;.;.;L;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D;T;T;D;T;D;D;T;T;T
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D
Polyphen		0.97	D;B;B;B;.;D;.;B;B;.
Vest4		0.91
MutPred		0.47		Loss of stability (P = 0.0506);.;.;Loss of stability (P = 0.0506);.;Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);.;.;.;
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		5.5
gMVP		0.85

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: rs758034895; hg19: chr1-204921199;