chr1-204954892-C-T

Position:

chr1-204954892-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.28

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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=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 GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFASC	NM_001005388.3 linkuse as main transcript	c.476C>T	p.Thr159Met	missense_variant	7/30	ENST00000339876.11	NP_001005388.2
NFASC	NM_001160331.2 linkuse as main transcript	c.458C>T	p.Thr153Met	missense_variant	5/28	ENST00000539706.6	NP_001153803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFASC	ENST00000339876.11 linkuse as main transcript	c.476C>T	p.Thr159Met	missense_variant	7/30	5	NM_001005388.3	ENSP00000344786		O94856-9
NFASC	ENST00000539706.6 linkuse as main transcript	c.458C>T	p.Thr153Met	missense_variant	5/28	5	NM_001160331.2	ENSP00000438614	A2	O94856-11

Frequencies

GnomAD3 genomes

AF:

0.00906

AC:

1379

AN:

152154

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0103

AC XY:

1402

AN XY:

135910

show subpopulations

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.:

AF XY:

0.00853

AC XY:

6200

AN XY:

727232

show subpopulations

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.:

Cov.:

AF XY:

0.0112

AC XY:

836

AN XY:

74434

show subpopulations

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.:

Bravo

AF:

0.00444

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00941

AC:

1142

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.00758

EpiControl

AF:

0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NFASC: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;.;.;.;.;.;.;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.78

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

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over