1-204928444-G-C

Variant names:

• chr1-204928444-G-C
• rs2802853
• NM_001005388.3:c.-91+7704G>C

Variant summary

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

The NM_001005388.3(NFASC):​c.-91+7704G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 151,956 control chromosomes in the GnomAD database, including 21,813 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 0.51 (21813 hom., cov: 31)
• Consequence: NFASC NM_001005388.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.577
• Publications: 6 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.646 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.-91+7704G>C		intron	N/A	NP_001005388.2	O94856-9
	NFASC	NM_001160331.2	MANE Plus Clinical	c.-90-15782G>C		intron	N/A	NP_001153803.1	O94856-11
	NFASC	NM_001378329.1		c.-91+7704G>C		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.-91+7704G>C		intron	N/A	ENSP00000344786.6	O94856-9
	NFASC	ENST00000539706.6	TSL:5 MANE Plus Clinical	c.-90-15782G>C		intron	N/A	ENSP00000438614.2	O94856-11
	NFASC	ENST00000401399.5	TSL:1	c.-91+7704G>C		intron	N/A	ENSP00000385637.1	O94856-9

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78116 AN: 151836 Hom.: 21815 Cov.: 31

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.524

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

GnomAD4 genome AF: 0.514 AC: 78127 AN: 151956 Hom.: 21813 Cov.: 31 AF XY: 0.506 AC XY: 37551 AN XY: 74234

African (AFR) AF: 0.332 AC: 13752 AN: 41444

American (AMR) AF: 0.476 AC: 7269 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 1938 AN: 3468

East Asian (EAS) AF: 0.214 AC: 1105 AN: 5164

South Asian (SAS) AF: 0.461 AC: 2216 AN: 4810

European-Finnish (FIN) AF: 0.558 AC: 5878 AN: 10534

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44206 AN: 67946

Other (OTH) AF: 0.519 AC: 1092 AN: 2104

Alfa AF: 0.575 Hom.: 3194

Bravo AF: 0.500

Asia WGS AF: 0.325 AC: 1134 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.74
DANN	Benign	0.63
PhyloP100		-0.58
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: rs2802853; hg19: chr1-204897572; COSMIC: COSV58362053; COSMIC: COSV58362053;