NM_018723.4:c.142C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_018723.4(RBFOX1):c.142C>T(p.Pro48Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,614,040 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. P48P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00068 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00094 ( 1 hom. )

Consequence

RBFOX1
NM_018723.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 7.31

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.063970596).

BP6

Variant 16-7518261-C-T is Benign according to our data. Variant chr16-7518261-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 410097.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 104 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4 link	c.142C>T	p.Pro48Ser	missense_variant	Exon 5 of 16	ENST00000550418.6	NP_061193.2	Q9NWB1-1Q59HD3
RBFOX1	NM_145893.3 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 2 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.142C>T	p.Pro48Ser	missense_variant	Exon 5 of 16	1	NM_018723.4	ENSP00000450031.1		Q9NWB1-1
RBFOX1	ENST00000355637.9 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 2 of 14	1	NM_145893.3	ENSP00000347855.4		Q9NWB1-5

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000649

AC:

163

AN:

251338

AF XY:

0.000663

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.000906

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000936

AC:

1369

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000897

AC XY:

652

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000402

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000955

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00106

AC:

1182

AN:

1111992

Other (OTH)

AF:

0.000861

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

172

259

345

431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

144

192

240

<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:

0.000683

AC:

104

AN:

152176

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41438

American (AMR)

AF:

0.000458

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000997

Hom.:

Bravo

AF:

0.000733

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000552

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RBFOX1-related disorder

Benign:1

Nov 14, 2023

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

Oct 07, 2024

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

0.088

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

.;.;.;T;.;T;.;.;.;T;.;.;.;.;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.064

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.2

.;.;M;M;.;.;.;.;.;M;.;.;.;.;.;.

PhyloP100

7.3

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.4

.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.

REVEL

Benign

0.22

Sift

Benign

0.053

.;T;D;D;D;D;D;D;D;D;T;T;T;D;.;.

Sift4G

Benign

0.23

.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.70, 0.98, 1.0, 1.0, 0.98, 1.0

.;.;P;D;D;D;D;.;.;D;D;D;D;.;.;.

Vest4

0.60, 0.74, 0.66, 0.65, 0.65, 0.67, 0.74, 0.61, 0.63, 0.68, 0.57, 0.66

MVP

0.15

MPC

0.017

ClinPred

0.12

GERP RS

4.8

Varity_R

0.35

gMVP

0.56

Mutation Taster

=33/67

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over