rs1555812114

Positions:

• chr16-7709100-C-T

Variant summary

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

The NM_018723.4(RBFOX1):​c.1040C>T​(p.Ala347Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RBFOX1 NM_018723.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.44

Genes affected

RBFOX1 (HGNC:18222): (RNA binding fox-1 homolog 1) The Fox-1 family of RNA-binding proteins is evolutionarily conserved, and regulates tissue-specific alternative splicing in metazoa. Fox-1 recognizes a (U)GCAUG stretch in regulated exons or in flanking introns. The protein binds to the C-terminus of ataxin-2 and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the product of the SCA2 gene which causes familial neurodegenerative diseases. Fox-1 and ataxin-2 are both localized in the trans-Golgi network. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX1	NM_018723.4	c.1040C>T	p.Ala347Val	missense_variant	15/16	ENST00000550418.6
RBFOX1	NM_145893.3	c.1156C>T	p.Leu386Phe	missense_variant	13/14	ENST00000355637.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX1	ENST00000550418.6	c.1040C>T	p.Ala347Val	missense_variant	15/16	1	NM_018723.4	A1
RBFOX1	ENST00000355637.9	c.1156C>T	p.Leu386Phe	missense_variant	13/14	1	NM_145893.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461228 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RBFOX1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 368 of the RBFOX1 protein (p.Ala368Val). 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	0.12
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N;N;.
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D;D
Polyphen		0.40	B;B;P;B;P;P;.;.
Vest4		0.74
MutPred		0.34		.;.;Loss of disorder (P = 0.0538);.;.;.;.;.;
MVP		0.23
MPC		1.5
ClinPred		0.70	D
GERP RS		5.7
Varity_R		0.20
gMVP		0.19

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: rs1555812114; hg19: chr16-7759102;