chr1-204997300-C-G

Position:

• chr1-204997300-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 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. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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 Benign. Variant got -11 ACMG points.

• 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.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFASC	NM_001005388.3	c.2913C>G	p.Ile971Met	missense_variant	25/30	ENST00000339876.11	NP_001005388.2
NFASC	NM_001160331.2	c.3136+5994C>G		intron_variant		ENST00000539706.6	NP_001153803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFASC	ENST00000339876.11	c.2913C>G	p.Ile971Met	missense_variant	25/30	5	NM_001005388.3	ENSP00000344786
NFASC	ENST00000539706.6	c.3136+5994C>G		intron_variant		5	NM_001160331.2	ENSP00000438614	A2

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

GnomAD3 exomes AF: 0.305 AC: 68054 AN: 223492 Hom.: 10498 AF XY: 0.305 AC XY: 37288 AN XY: 122060

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 SAS exome AF: 0.320

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

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.291

Gnomad4 ASJ exome AF: 0.320

Gnomad4 EAS exome AF: 0.483

Gnomad4 SAS exome AF: 0.319

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.285

Gnomad4 OTH exome AF: 0.287

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

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.443

Gnomad4 SAS AF: 0.360

Gnomad4 FIN AF: 0.301

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.246

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 v4.3

Name	Calibrated prediction	Score	Prediction
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;.;T
MetaRNN	Benign	0.00051	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.23	N;N;N
REVEL	Benign	0.069
Sift	Benign	0.23	T;T;D
Sift4G	Benign	0.25	T;T;D
Polyphen		0.0020	B;B;.
Vest4		0.21
MPC		0.38
ClinPred		0.0029	T
GERP RS		0.39
gMVP		0.26

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: rs2802808; hg19: chr1-204966428; COSMIC: COSV58360557;