chr1-204997300-C-G

Variant names:

• chr1-204997300-C-G
• rs2802808
• NM_001005388.3:c.2913C>G

Variant summary

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

The NM_001005388.3(NFASC):​c.2913C>G​(p.Ile971Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,602,174 control chromosomes in the GnomAD database, including 69,032 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I971I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (5914 hom., cov: 31)
  • Exomes 𝑓: 0.29 (63118 hom.)
• Consequence: NFASC NM_001005388.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 19 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 (MetaRNN=5.056262E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 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.2913C>G	p.Ile971Met	missense	Exon 25 of 30	NP_001005388.2	O94856-9
	NFASC	NM_001160331.2	MANE Plus Clinical	c.3136+5994C>G		intron	N/A	NP_001153803.1	O94856-11
	NFASC	NM_001378329.1		c.3234C>G	p.Ile1078Met	missense	Exon 27 of 32	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.2913C>G	p.Ile971Met	missense	Exon 25 of 30	ENSP00000344786.6	O94856-9
	NFASC	ENST00000401399.5	TSL:1	c.2913C>G	p.Ile971Met	missense	Exon 24 of 29	ENSP00000385637.1	O94856-9
	NFASC	ENST00000447819.1	TSL:1	c.117C>G	p.Ile39Met	missense	Exon 1 of 4	ENSP00000416891.1	A0A0C4DG92

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41709 AN: 151878 Hom.: 5904 Cov.: 31

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.305 AC: 68054 AN: 223492 AF XY: 0.305

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.442

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.291

GnomAD4 exome AF: 0.291 AC: 422427 AN: 1450178 Hom.: 63118 Cov.: 37 AF XY: 0.292 AC XY: 210257 AN XY: 720660

African (AFR) AF: 0.202 AC: 6675 AN: 33122

American (AMR) AF: 0.291 AC: 12424 AN: 42704

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8302 AN: 25926

East Asian (EAS) AF: 0.483 AC: 18688 AN: 38722

South Asian (SAS) AF: 0.319 AC: 27162 AN: 85158

European-Finnish (FIN) AF: 0.302 AC: 15770 AN: 52282

Middle Eastern (MID) AF: 0.218 AC: 1258 AN: 5758

European-Non Finnish (NFE) AF: 0.285 AC: 314947 AN: 1106618

Other (OTH) AF: 0.287 AC: 17201 AN: 59888

GnomAD4 genome AF: 0.275 AC: 41730 AN: 151996 Hom.: 5914 Cov.: 31 AF XY: 0.280 AC XY: 20829 AN XY: 74300

African (AFR) AF: 0.213 AC: 8836 AN: 41450

American (AMR) AF: 0.269 AC: 4103 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1101 AN: 3466

East Asian (EAS) AF: 0.443 AC: 2280 AN: 5146

South Asian (SAS) AF: 0.360 AC: 1733 AN: 4808

European-Finnish (FIN) AF: 0.301 AC: 3184 AN: 10580

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19616 AN: 67950

Other (OTH) AF: 0.246 AC: 519 AN: 2114

Alfa AF: 0.259 Hom.: 1860

Bravo AF: 0.267

TwinsUK AF: 0.270 AC: 1002

ALSPAC AF: 0.285 AC: 1097

ESP6500AA AF: 0.216 AC: 676

ESP6500EA AF: 0.284 AC: 2031

ExAC AF: 0.288 AC: 34575

Asia WGS AF: 0.383 AC: 1334 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.00051	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.19
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.069
Sift	Benign	0.23	T
Sift4G	Benign	0.25	T
Polyphen		0.0020	B
Vest4		0.21
MPC		0.38
ClinPred		0.0029	T
GERP RS		0.39
PromoterAI		0.022	Neutral
gMVP		0.26
Mutation Taster		=97/3	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: rs2802808; hg19: chr1-204966428; COSMIC: COSV58360557;