1-204944337-C-T

Position:

chr1-204944337-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The NM_001005388.3(NFASC):c.22C>T(p.Pro8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,613,840 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 3 hom. )

Consequence

NFASC
NM_001005388.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 2.30

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 -8 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=0.008660942).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000309 (47/152320) while in subpopulation SAS AF= 0.0058 (28/4824). AF 95% confidence interval is 0.00413. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFASC	NM_001005388.3 linkuse as main transcript	c.22C>T	p.Pro8Ser	missense_variant	3/30	ENST00000339876.11	NP_001005388.2
NFASC	NM_001160331.2 linkuse as main transcript	c.22C>T	p.Pro8Ser	missense_variant	2/28	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.22C>T	p.Pro8Ser	missense_variant	3/30	5	NM_001005388.3	ENSP00000344786		O94856-9
NFASC	ENST00000539706.6 linkuse as main transcript	c.22C>T	p.Pro8Ser	missense_variant	2/28	5	NM_001160331.2	ENSP00000438614	A2	O94856-11

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000537

AC:

134

AN:

249632

Hom.:

AF XY:

0.000696

AC XY:

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00325

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.000332

AC:

485

AN:

1461520

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

299

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00353

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.000309

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000210

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with central and peripheral motor dysfunction

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with central and peripheral motor dysfunction (MIM#618356). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (138 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 06, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

NFASC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.016

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

D;D;D;D;D;.;D;.;.

M_CAP

Benign

0.046

MetaRNN

Benign

0.0087

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.34

N;N;N;N;N;N;.;N;N

MutationTaster

Benign

0.98

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

0.92

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.049

Sift

Benign

0.18

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.67

T;T;T;T;T;T;T;T;T

Polyphen

0.91

P;B;B;B;.;P;.;B;B

Vest4

0.41

MVP

0.53

MPC

0.96

ClinPred

0.036

GERP RS

5.0

gMVP

0.45

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