1-204954892-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005388.3(NFASC):c.476C>T(p.Thr159Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00858 in 1,614,124 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0091 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (105 hom.)
• Consequence: NFASC NM_001005388.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.28

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NFASC
• BP4: Computational evidence support a benign effect (MetaRNN=0.005971402).
• BP6: Variant 1-204954892-C-T is Benign according to our data. Variant chr1-204954892-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 709848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00908 (1382/152272) while in subpopulation SAS AF= 0.0104 (50/4828). AF 95% confidence interval is 0.00807. There are 32 homozygotes in gnomad4. There are 836 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFASC	NM_001005388.3	c.476C>T	p.Thr159Met	missense_variant	7/30	ENST00000339876.11
NFASC	NM_001160331.2	c.458C>T	p.Thr153Met	missense_variant	5/28	ENST00000539706.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFASC	ENST00000339876.11	c.476C>T	p.Thr159Met	missense_variant	7/30	5	NM_001005388.3
NFASC	ENST00000539706.6	c.458C>T	p.Thr153Met	missense_variant	5/28	5	NM_001160331.2	A2

Frequencies

GnomAD3 genomes AF: 0.00906 AC: 1379 AN: 152154 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00982

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.0560

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00806

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0100 AC: 2521 AN: 251476 Hom.: 27 AF XY: 0.0103 AC XY: 1402 AN XY: 135910

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.00375

Gnomad SAS exome AF: 0.00931

Gnomad FIN exome AF: 0.0501

Gnomad NFE exome AF: 0.00766

Gnomad OTH exome AF: 0.00977

GnomAD4 exome AF: 0.00853 AC: 12465 AN: 1461852 Hom.: 105 Cov.: 33 AF XY: 0.00853 AC XY: 6200 AN XY: 727232

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.0185

Gnomad4 SAS exome AF: 0.00926

Gnomad4 FIN exome AF: 0.0470

Gnomad4 NFE exome AF: 0.00696

Gnomad4 OTH exome AF: 0.00638

GnomAD4 genome AF: 0.00908 AC: 1382 AN: 152272 Hom.: 32 Cov.: 32 AF XY: 0.0112 AC XY: 836 AN XY: 74434

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0560

Gnomad4 NFE AF: 0.00806

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00697 Hom.: 12

Bravo AF: 0.00444

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00941 AC: 1142

Asia WGS AF: 0.00953 AC: 34 AN: 3478

EpiCase AF: 0.00758

EpiControl AF: 0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NFASC: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.;.;D
MetaRNN	Benign	0.0060	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.;L;.;L;.;.;.
MutationTaster	Benign	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.21	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.080
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;.;D;D;D;.
Vest4		0.42
MPC		1.1
ClinPred		0.029	T
GERP RS		5.5
gMVP		0.20

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: rs3795564; hg19: chr1-204924020;