rs766496349

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_018723.4(RBFOX1):c.1006G>C(p.Val336Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

RBFOX1
NM_018723.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.18

Publications

0 publications found

Variant links:

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]

RBFOX1 Gene-Disease associations (from GenCC):

epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P
autism susceptibility 1
Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

RBFOX1 links:

ENSG00000301273 (HGNC:):

ENSG00000301273 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17683661).

BS2

High AC in GnomAdExome4 at 53 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4 link	c.1006G>C	p.Val336Leu	missense_variant	Exon 15 of 16	ENST00000550418.6	NP_061193.2	Q9NWB1-1Q59HD3
RBFOX1	NM_145893.3 link	c.1122G>C	p.Glu374Asp	missense_variant	Exon 13 of 14	ENST00000355637.9	NP_665900.1	Q9NWB1-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6 link	c.1006G>C	p.Val336Leu	missense_variant	Exon 15 of 16	1	NM_018723.4	ENSP00000450031.1		Q9NWB1-1
RBFOX1	ENST00000355637.9 link	c.1122G>C	p.Glu374Asp	missense_variant	Exon 13 of 14	1	NM_145893.3	ENSP00000347855.4		Q9NWB1-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000637

AC:

AN:

251224

AF XY:

0.0000442

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461458

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000396

AC:

AN:

1111682

Other (OTH)

AF:

0.000133

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Idiopathic generalized epilepsy

Uncertain:1

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 357 of the RBFOX1 protein (p.Val357Leu). This variant is present in population databases (rs766496349, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RBFOX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 529514). 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

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

7.2

PROVEAN

Benign

-0.36

.;N;N;N;N

REVEL

Benign

0.23

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Benign

0.13

.;T;D;T;T

Polyphen

0.0040, 0.0020

.;.;B;.;B

Vest4

0.60, 0.61, 0.57, 0.58

MutPred

0.17

.;.;Gain of disorder (P = 0.2226);.;.;

MVP

0.79

ClinPred

0.16

GERP RS

5.7

Varity_R

0.47

Mutation Taster

=63/37

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over