1-204952130-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001005388.3(NFASC):c.215+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,588,814 control chromosomes in the GnomAD database, including 140,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (9796 hom., cov: 32)
  • Exomes 𝑓: 0.42 (130968 hom.)
• Consequence: NFASC NM_001005388.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.365

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-204952130-A-G is Benign according to our data. Variant chr1-204952130-A-G is described in ClinVar as [Benign]. Clinvar id is 1325900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFASC	NM_001005388.3	c.215+14A>G		intron_variant		ENST00000339876.11
NFASC	NM_001160331.2	c.197+14A>G		intron_variant		ENST00000539706.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFASC	ENST00000339876.11	c.215+14A>G		intron_variant		5	NM_001005388.3
NFASC	ENST00000539706.6	c.197+14A>G		intron_variant		5	NM_001160331.2	A2

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49872 AN: 151950 Hom.: 9798 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.0822

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.374 AC: 92826 AN: 248338 Hom.: 19076 AF XY: 0.384 AC XY: 51534 AN XY: 134094

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.0797

Gnomad SAS exome AF: 0.420

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.447

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.418 AC: 601165 AN: 1436746 Hom.: 130968 Cov.: 25 AF XY: 0.420 AC XY: 300766 AN XY: 715908

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 0.0790

Gnomad4 SAS exome AF: 0.417

Gnomad4 FIN exome AF: 0.429

Gnomad4 NFE exome AF: 0.444

Gnomad4 OTH exome AF: 0.402

GnomAD4 genome AF: 0.328 AC: 49880 AN: 152068 Hom.: 9796 Cov.: 32 AF XY: 0.325 AC XY: 24146 AN XY: 74324

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.0820

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.445

Gnomad4 OTH AF: 0.339

Alfa AF: 0.417 Hom.: 6982

Bravo AF: 0.308

Asia WGS AF: 0.232 AC: 808 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with central and peripheral motor dysfunction Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.5
Dann	Benign	0.76

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: rs12141283; hg19: chr1-204921258; COSMIC: COSV58362107; COSMIC: COSV58362107;