16-7709117-G-A

Variant names:

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

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

RBFOX1 links:

ENSG00000301273 (HGNC:):

ENSG00000301273 links:

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 ClinVar as Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018723.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBFOX1	NM_018723.4	MANE Select	c.1057G>A	p.Gly353Ser	missense	Exon 15 of 16	NP_061193.2
RBFOX1	NM_145893.3	MANE Plus Clinical	c.1173G>A	p.Thr391Thr	synonymous	Exon 13 of 14	NP_665900.1	Q9NWB1-5
RBFOX1	NM_001415888.1		c.1573G>A	p.Gly525Ser	missense	Exon 17 of 18	NP_001402817.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBFOX1	ENST00000550418.6	TSL:1 MANE Select	c.1057G>A	p.Gly353Ser	missense	Exon 15 of 16	ENSP00000450031.1	Q9NWB1-1
RBFOX1	ENST00000311745.9	TSL:1	c.1120G>A	p.Gly374Ser	missense	Exon 12 of 13	ENSP00000309117.5	Q9NWB1-2
RBFOX1	ENST00000436368.6	TSL:1	c.1120G>A	p.Gly374Ser	missense	Exon 12 of 13	ENSP00000402745.2	Q9NWB1-4

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

228

AN:

152056

Hom.:

Cov.:

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.:

Cov.:

AF XY:

0.00193

AC XY:

1406

AN XY:

726692

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33450

American (AMR)

AF:

0.00204

AC:

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26130

East Asian (EAS)

AF:

0.000303

AC:

AN:

39650

South Asian (SAS)

AF:

0.00158

AC:

136

AN:

86090

European-Finnish (FIN)

AF:

0.000506

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00295

AC:

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

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

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.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

41524

American (AMR)

AF:

0.00105

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.000581

AC:

AN:

5162

South Asian (SAS)

AF:

0.00228

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00201

AC:

137

AN:

68002

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00191

AC:

232

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00309

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Idiopathic generalized epilepsy (1)

RBFOX1-related disorder (1)

Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.047

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0088

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.5

PhyloP100

2.6

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.74

REVEL

Benign

0.026

Sift

Benign

0.59

Sift4G

Benign

0.64

Polyphen

0.055

Vest4

0.38

MVP

0.23

MPC

0.70

ClinPred

0.0081

GERP RS

3.6

Varity_R

0.060

gMVP

0.18

Mutation Taster

=79/21

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over