1-204952130-A-G

Variant names:

• chr1-204952130-A-G
• rs12141283
• NM_001005388.3:c.215+14A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• 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

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
NFASC	NM_001005388.3	c.215+14A>G		intron_variant	Intron 5 of 29	ENST00000339876.11	NP_001005388.2
NFASC	NM_001160331.2	c.197+14A>G		intron_variant	Intron 3 of 27	ENST00000539706.6	NP_001153803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFASC	ENST00000339876.11	c.215+14A>G		intron_variant	Intron 5 of 29	5	NM_001005388.3	ENSP00000344786.6
NFASC	ENST00000539706.6	c.197+14A>G		intron_variant	Intron 3 of 27	5	NM_001160331.2	ENSP00000438614.2

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

GnomAD2 exomes AF: 0.374 AC: 92826 AN: 248338 AF XY: 0.384

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 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 AC: 4096 AN: 32962

Gnomad4 AMR exome AF: 0.316 AC: 14015 AN: 44410

Gnomad4 ASJ exome AF: 0.429 AC: 11141 AN: 25956

Gnomad4 EAS exome AF: 0.0790 AC: 3124 AN: 39532

Gnomad4 SAS exome AF: 0.417 AC: 35656 AN: 85482

Gnomad4 FIN exome AF: 0.429 AC: 22859 AN: 53298

Gnomad4 NFE exome AF: 0.444 AC: 484061 AN: 1089810

Gnomad4 Remaining exome AF: 0.402 AC: 23930 AN: 59576

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 AC: 0.13286 AN: 0.13286

Gnomad4 AMR AF: 0.315 AC: 0.314611 AN: 0.314611

Gnomad4 ASJ AF: 0.428 AC: 0.427624 AN: 0.427624

Gnomad4 EAS AF: 0.0820 AC: 0.0820433 AN: 0.0820433

Gnomad4 SAS AF: 0.404 AC: 0.404189 AN: 0.404189

Gnomad4 FIN AF: 0.409 AC: 0.40866 AN: 0.40866

Gnomad4 NFE AF: 0.445 AC: 0.445265 AN: 0.445265

Gnomad4 OTH AF: 0.339 AC: 0.339048 AN: 0.339048

Alfa AF: 0.418 Hom.: 7710

Bravo AF: 0.308

Asia WGS AF: 0.232 AC: 808 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with central and peripheral motor dysfunction Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.76
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

Publications

LitVar

Other links and lift over

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