chr1-204952014-C-T

Variant names:

• chr1-204952014-C-T
• rs564513596
• NM_001005388.3:c.113C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005388.3(NFASC):​c.113C>T​(p.Thr38Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NFASC NM_001005388.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09138307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFASC	NM_001005388.3	c.113C>T	p.Thr38Met	missense_variant	Exon 5 of 30	ENST00000339876.11	NP_001005388.2
NFASC	NM_001160331.2	c.95C>T	p.Thr32Met	missense_variant	Exon 3 of 28	ENST00000539706.6	NP_001153803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFASC	ENST00000339876.11	c.113C>T	p.Thr38Met	missense_variant	Exon 5 of 30	5	NM_001005388.3	ENSP00000344786.6
NFASC	ENST00000539706.6	c.95C>T	p.Thr32Met	missense_variant	Exon 3 of 28	5	NM_001160331.2	ENSP00000438614.2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251126 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135730

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461606 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727084

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74460

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113C>T (p.T38M) alteration is located in exon 5 (coding exon 3) of the NFASC gene. This alteration results from a C to T substitution at nucleotide position 113, causing the threonine (T) at amino acid position 38 to be replaced by a methionine (M). 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	-0.26	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;.;.;.;.;.;.;.;.;T
Eigen	Benign	-0.072
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;D;.;.;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.091	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.0	N;.;.;N;.;N;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.49	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.054
Sift	Benign	0.086	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T;T;T;T;T
Polyphen		0.13	B;B;B;P;.;B;.;B;B;.
Vest4		0.28
MVP		0.60
MPC		0.52
ClinPred		0.084	T
GERP RS		4.6
gMVP		0.22

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: rs564513596; hg19: chr1-204921142;