Genetic Variant NFASC:p.Thr38Lys (chr1-204952014-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001005388.3(NFASC):c.113C>A(p.Thr38Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T38M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NFASC
NM_001005388.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.76

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with central and peripheral motor dysfunction
Inheritance: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

NFASC links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.094436795).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005388.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFASC	NM_001005388.3	MANE Select	c.113C>A	p.Thr38Lys	missense	Exon 5 of 30	NP_001005388.2	O94856-9
NFASC	NM_001160331.2	MANE Plus Clinical	c.95C>A	p.Thr32Lys	missense	Exon 3 of 28	NP_001153803.1	O94856-11
NFASC	NM_001378329.1		c.113C>A	p.Thr38Lys	missense	Exon 5 of 32	NP_001365258.1	O94856-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFASC	ENST00000339876.11	TSL:5 MANE Select	c.113C>A	p.Thr38Lys	missense	Exon 5 of 30	ENSP00000344786.6	O94856-9
NFASC	ENST00000539706.6	TSL:5 MANE Plus Clinical	c.95C>A	p.Thr32Lys	missense	Exon 3 of 28	ENSP00000438614.2	O94856-11
NFASC	ENST00000401399.5	TSL:1	c.113C>A	p.Thr38Lys	missense	Exon 4 of 29	ENSP00000385637.1	O94856-9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.083

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.061

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0098

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.0

PhyloP100

2.8

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.57

REVEL

Benign

0.062

Sift

Benign

0.23

Sift4G

Benign

1.0

Polyphen

0.032

Vest4

0.20

MutPred

0.32

Gain of methylation at T38 (P = 0.017)

MVP

0.49

MPC

0.45

ClinPred

0.20

GERP RS

4.6

gMVP

0.25

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over