chr1-204954348-A-G

Position:

• chr1-204954348-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001005388.3(NFASC):​c.376A>G​(p.Thr126Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T126M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFASC NM_001005388.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.99

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.39856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFASC	NM_001005388.3	c.376A>G	p.Thr126Ala	missense_variant	6/30	ENST00000339876.11
NFASC	NM_001160331.2	c.358A>G	p.Thr120Ala	missense_variant	4/28	ENST00000539706.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFASC	ENST00000339876.11	c.376A>G	p.Thr126Ala	missense_variant	6/30	5	NM_001005388.3
NFASC	ENST00000539706.6	c.358A>G	p.Thr120Ala	missense_variant	4/28	5	NM_001160331.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.376A>G (p.T126A) alteration is located in exon 6 (coding exon 4) of the NFASC gene. This alteration results from a A to G substitution at nucleotide position 376, causing the threonine (T) at amino acid position 126 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0041	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;.;T;.;.;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.6	L;.;.;L;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.57	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T;T;D;T;T;T
Polyphen		0.92	P;P;P;B;.;P;.;P;P;.
Vest4		0.54
MutPred		0.44		Gain of ubiquitination at K123 (P = 0.0773);.;.;Gain of ubiquitination at K123 (P = 0.0773);.;Gain of ubiquitination at K123 (P = 0.0773);Gain of ubiquitination at K123 (P = 0.0773);.;.;.;
MVP		0.74
MPC		1.2
ClinPred		0.86	D
GERP RS		5.4
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-204923476;