rs878854171

Variant names:

• chr17-79115648-G-A
• rs878854171
• NM_001350451.2:c.68C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001350451.2(RBFOX3):​c.68C>T​(p.Ala23Val) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBFOX3 NM_001350451.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81
• Publications: 0 publications found

Genes affected

RBFOX3 (HGNC:27097): (RNA binding fox-1 homolog 3) This gene encodes a member of the RNA-binding FOX protein family which is involved in the regulation of alternative splicing of pre-mRNA. The protein has an N-terminal proline-rich region, an RNA recognition motif (RRM) domain, and a C-terminal alanine-rich region. This gene produces the neuronal nuclei (NeuN) antigen that has been widely used as a marker for post-mitotic neurons. This gene has its highest expression in the central nervous system and plays a prominent role in neural tissue development and regulation of adult brain function. Mutations in this gene have been associated with numerous neurological disorders. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2017]

RBFOX3 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05807075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX3	NM_001350451.2	c.68C>T	p.Ala23Val	missense_variant	Exon 5 of 15	ENST00000693108.1	NP_001337380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX3	ENST00000693108.1	c.68C>T	p.Ala23Val	missense_variant	Exon 5 of 15		NM_001350451.2	ENSP00000510395.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1194202 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 583744

African (AFR) AF: 0.00 AC: 0 AN: 24960

American (AMR) AF: 0.00 AC: 0 AN: 21674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16890

East Asian (EAS) AF: 0.00 AC: 0 AN: 24160

South Asian (SAS) AF: 0.00 AC: 0 AN: 63794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 966220

Other (OTH) AF: 0.00 AC: 0 AN: 48144

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy Uncertain:1

Jan 31, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. While this variant is not present in population databases (ExAC), the frequency information is unreliable due to low sequence quality at this site. This sequence change replaces alanine with valine at codon 23 of the RBFOX3 protein (p.Ala23Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.028	.;.;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.058	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;.;L;L
PhyloP100		1.8
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.073	T;T;T;T
Polyphen		0.0010	.;.;B;.
Vest4		0.17
MutPred		0.18		Loss of glycosylation at P24 (P = 0.1886);Loss of glycosylation at P24 (P = 0.1886);Loss of glycosylation at P24 (P = 0.1886);Loss of glycosylation at P24 (P = 0.1886);
MVP		0.055
ClinPred		0.075	T
GERP RS		0.89
PromoterAI		-0.019	Neutral
Varity_R		0.065
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs878854171; hg19: chr17-77111730;