16-7333047-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_145893.3(RBFOX1):c.46A>G(p.Met16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RBFOX1 NM_145893.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.74

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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX1	NM_145893.3	c.46A>G	p.Met16Val	missense_variant	1/14	ENST00000355637.9
RBFOX1	NM_018723.4	c.28-185100A>G		intron_variant		ENST00000550418.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX1	ENST00000355637.9	c.46A>G	p.Met16Val	missense_variant	1/14	1	NM_145893.3
RBFOX1	ENST00000550418.6	c.28-185100A>G		intron_variant		1	NM_018723.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250786 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135514

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727136

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.46A>G (p.M16V) alteration is located in exon 1 (coding exon 1) of the RBFOX1 gene. This alteration results from a A to G substitution at nucleotide position 46, causing the methionine (M) at amino acid position 16 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Idiopathic generalized epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 11, 2022

ClinVar contains an entry for this variant (Variation ID: 460032). This variant has not been reported in the literature in individuals affected with RBFOX1-related conditions. This variant is present in population databases (rs779418628, gnomAD 0.003%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 16 of the RBFOX1 protein (p.Met16Val). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T;T;T;D;D
M_CAP	Benign	0.0045	T
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.59	N;N;N;N;.
REVEL	Benign	0.16
Sift	Benign	0.70	T;T;T;D;.
Sift4G	Benign	1.0	T;T;T;D;D
Polyphen		0.0070	B;B;B;.;.
Vest4		0.35
MutPred		0.97		.;.;.;Loss of disorder (P = 0.075);Loss of disorder (P = 0.075);
MVP		0.50
MPC		0.0041
ClinPred		0.19	T
GERP RS		5.8

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: rs779418628; hg19: chr16-7383048;