rs2887480

Variant names:

• chr1-204912210-C-T
• rs2887480
• NM_001005388.3:c.-199-8422C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001005388.3(NFASC):​c.-199-8422C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 150,970 control chromosomes in the GnomAD database, including 15,340 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (15340 hom., cov: 28)
• Consequence: NFASC NM_001005388.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.286
• Publications: 3 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005388.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFASC	NM_001005388.3	MANE Select	c.-199-8422C>T		intron	N/A	NP_001005388.2	O94856-9
	NFASC	NM_001160331.2	MANE Plus Clinical	c.-90-32016C>T		intron	N/A	NP_001153803.1	O94856-11
	NFASC	NM_001378329.1		c.-199-8422C>T		intron	N/A	NP_001365258.1	O94856-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFASC	ENST00000339876.11	TSL:5 MANE Select	c.-199-8422C>T		intron	N/A	ENSP00000344786.6	O94856-9
	NFASC	ENST00000539706.6	TSL:5 MANE Plus Clinical	c.-90-32016C>T		intron	N/A	ENSP00000438614.2	O94856-11
	NFASC	ENST00000513543.6	TSL:1	c.-199-8422C>T		intron	N/A	ENSP00000425908.1	O94856-3

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67223 AN: 150854 Hom.: 15324 Cov.: 28

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.479

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.446 AC: 67282 AN: 150970 Hom.: 15340 Cov.: 28 AF XY: 0.447 AC XY: 32954 AN XY: 73662

African (AFR) AF: 0.377 AC: 15486 AN: 41026

American (AMR) AF: 0.551 AC: 8355 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1608 AN: 3470

East Asian (EAS) AF: 0.465 AC: 2377 AN: 5114

South Asian (SAS) AF: 0.375 AC: 1793 AN: 4784

European-Finnish (FIN) AF: 0.473 AC: 4862 AN: 10274

Middle Eastern (MID) AF: 0.486 AC: 139 AN: 286

European-Non Finnish (NFE) AF: 0.461 AC: 31259 AN: 67856

Other (OTH) AF: 0.481 AC: 1007 AN: 2094

Alfa AF: 0.453 Hom.: 7848

Bravo AF: 0.452

Asia WGS AF: 0.453 AC: 1576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.49
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs2887480; hg19: chr1-204881338;