chr16-7709117-G-A

Variant names:

• chr16-7709117-G-A
• rs145873257
• NM_018723.4:c.1057G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 2.56
• Publications: 6 publications found

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

ENSG00000301273 (HGNC:):

ACMG classification

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
RBFOX1	NM_018723.4	c.1057G>A	p.Gly353Ser	missense_variant	Exon 15 of 16	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.1173G>A	p.Thr391Thr	synonymous_variant	Exon 13 of 14	ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.1057G>A	p.Gly353Ser	missense_variant	Exon 15 of 16	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.1173G>A	p.Thr391Thr	synonymous_variant	Exon 13 of 14	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152056 Hom.: 1 Cov.: 31

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

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

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

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152172 Hom.: 1 Cov.: 31 AF XY: 0.00133 AC XY: 99 AN XY: 74398

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

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:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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

Other links and lift over

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