1-204944382-G-A

Variant names:

• chr1-204944382-G-A
• rs145678100
• NM_001005388.3:c.67G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001005388.3(NFASC):​c.67G>A​(p.Gly23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,608,018 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.00020 (1 hom.)
• Consequence: NFASC NM_001005388.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.541
• Publications: 4 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13341126).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000201 (293/1455770) while in subpopulation NFE AF = 0.000244 (271/1108974). AF 95% confidence interval is 0.00022. There are 1 homozygotes in GnomAdExome4. There are 125 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFASC	NM_001005388.3	c.67G>A	p.Gly23Arg	missense_variant	Exon 3 of 30	ENST00000339876.11	NP_001005388.2
NFASC	NM_001160331.2	c.67G>A	p.Gly23Arg	missense_variant	Exon 2 of 28	ENST00000539706.6	NP_001153803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFASC	ENST00000339876.11	c.67G>A	p.Gly23Arg	missense_variant	Exon 3 of 30	5	NM_001005388.3	ENSP00000344786.6
NFASC	ENST00000539706.6	c.67G>A	p.Gly23Arg	missense_variant	Exon 2 of 28	5	NM_001160331.2	ENSP00000438614.2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000102 AC: 25 AN: 244664 AF XY: 0.000128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000201 AC: 293 AN: 1455770 Hom.: 1 Cov.: 32 AF XY: 0.000173 AC XY: 125 AN XY: 723796

African (AFR) AF: 0.00 AC: 0 AN: 33186

American (AMR) AF: 0.000116 AC: 5 AN: 43202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39568

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85938

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53316

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5664

European-Non Finnish (NFE) AF: 0.000244 AC: 271 AN: 1108974

Other (OTH) AF: 0.000133 AC: 8 AN: 60082

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74460

African (AFR) AF: 0.0000481 AC: 2 AN: 41544

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.67G>A (p.G23R) alteration is located in exon 3 (coding exon 1) of the NFASC gene. This alteration results from a G to A substitution at nucleotide position 67, causing the glycine (G) at amino acid position 23 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jul 06, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.78	T;T;T;T;T;.;T;.;.
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.34	N;N;N;N;N;N;.;N;N
PhyloP100		0.54
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.085
Sift	Uncertain	0.015	D;T;T;T;T;D;T;T;T
Sift4G	Uncertain	0.0060	D;T;T;D;T;D;T;T;T
Polyphen		0.013	B;P;P;P;.;B;.;P;P
Vest4		0.37
MutPred		0.63		Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);
MVP		0.63
MPC		0.47
ClinPred		0.058	T
GERP RS		1.4
gMVP		0.48
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs145678100; hg19: chr1-204913510; COSMIC: COSV58364694; COSMIC: COSV58364694;