chr16-7709117-G-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_018723.4(RBFOX1):​c.1057G>A​(p.Gly353Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,612,934 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G353G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 31)
Exomes 𝑓: 0.0019 ( 7 hom. )

Consequence

RBFOX1
NM_018723.4 missense

Scores

2
17

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1B:4

Conservation

PhyloP100: 2.56

Publications

6 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010302544).
BP6
Variant 16-7709117-G-A is Benign according to our data. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709117-G-A is described in CliVar as Likely_benign. Clinvar id is 433121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 229 Unknown,AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBFOX1NM_018723.4 linkc.1057G>A p.Gly353Ser missense_variant Exon 15 of 16 ENST00000550418.6 NP_061193.2 Q9NWB1-1Q59HD3
RBFOX1NM_145893.3 linkc.1173G>A p.Thr391Thr synonymous_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
RBFOX1ENST00000550418.6 linkc.1057G>A p.Gly353Ser missense_variant Exon 15 of 16 1 NM_018723.4 ENSP00000450031.1 Q9NWB1-1
RBFOX1ENST00000355637.9 linkc.1173G>A p.Thr391Thr synonymous_variant Exon 13 of 14 1 NM_145893.3 ENSP00000347855.4 Q9NWB1-5

Frequencies

GnomAD3 genomes
AF:
0.00150
AC:
228
AN:
152056
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00126
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.000580
Gnomad SAS
AF:
0.00228
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00201
Gnomad OTH
AF:
0.00287
GnomAD2 exomes
AF:
0.00185
AC:
463
AN:
250768
AF XY:
0.00198
show subpopulations
Gnomad AFR exome
AF:
0.00135
Gnomad AMR exome
AF:
0.00180
Gnomad ASJ exome
AF:
0.000794
Gnomad EAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.000370
Gnomad NFE exome
AF:
0.00267
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.00192
AC:
2811
AN:
1460762
Hom.:
7
Cov.:
31
AF XY:
0.00193
AC XY:
1406
AN XY:
726692
show subpopulations
African (AFR)
AF:
0.00120
AC:
40
AN:
33450
American (AMR)
AF:
0.00204
AC:
91
AN:
44594
Ashkenazi Jewish (ASJ)
AF:
0.000727
AC:
19
AN:
26130
East Asian (EAS)
AF:
0.000303
AC:
12
AN:
39650
South Asian (SAS)
AF:
0.00158
AC:
136
AN:
86090
European-Finnish (FIN)
AF:
0.000506
AC:
27
AN:
53408
Middle Eastern (MID)
AF:
0.00295
AC:
17
AN:
5766
European-Non Finnish (NFE)
AF:
0.00212
AC:
2360
AN:
1111328
Other (OTH)
AF:
0.00181
AC:
109
AN:
60346
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.473
Heterozygous variant carriers
0
132
265
397
530
662
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
88
176
264
352
440
<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:
0.00150
AC:
229
AN:
152172
Hom.:
1
Cov.:
31
AF XY:
0.00133
AC XY:
99
AN XY:
74398
show subpopulations
African (AFR)
AF:
0.00128
AC:
53
AN:
41524
American (AMR)
AF:
0.00105
AC:
16
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3468
East Asian (EAS)
AF:
0.000581
AC:
3
AN:
5162
South Asian (SAS)
AF:
0.00228
AC:
11
AN:
4820
European-Finnish (FIN)
AF:
0.000189
AC:
2
AN:
10594
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00201
AC:
137
AN:
68002
Other (OTH)
AF:
0.00284
AC:
6
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
12
24
35
47
59
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00208
Hom.:
0
Bravo
AF:
0.00172
TwinsUK
AF:
0.00189
AC:
7
ALSPAC
AF:
0.00182
AC:
7
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00186
AC:
16
ExAC
AF:
0.00191
AC:
232
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00305
EpiControl
AF:
0.00309

ClinVar

Significance: Likely benign
Submissions summary: Pathogenic:1Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Nov 01, 2018
Athena Diagnostics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Self-limited epilepsy with centrotemporal spikes Pathogenic:1
Jan 01, 2017
Bioinformatics Core, Luxembourg Center for Systems Biomedicine
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:case-control

CAADphred>15 -

RBFOX1-related disorder Benign:1
Jul 28, 2022
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Idiopathic generalized epilepsy Benign:1
Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.053
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
21
DANN
Benign
0.95
DEOGEN2
Benign
0.047
.;T;T;T;.;.;.;.
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.10
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.90
D;.;D;D;D;D;D;D
M_CAP
Benign
0.0088
T
MetaRNN
Benign
0.010
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-1.5
.;N;.;N;.;.;.;.
PhyloP100
2.6
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.74
N;N;N;N;N;N;N;.
REVEL
Benign
0.026
Sift
Benign
0.59
T;T;T;T;T;T;T;.
Sift4G
Benign
0.64
T;T;T;T;T;T;T;T
Polyphen
0.055
B;B;P;B;P;B;.;.
Vest4
0.38
MVP
0.23
MPC
0.70
ClinPred
0.0081
T
GERP RS
3.6
Varity_R
0.060
gMVP
0.18
Mutation Taster
=79/21
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

Publications

Other links and lift over

dbSNP: rs145873257; hg19: chr16-7759119; COSMIC: COSV60957463; API