rs368460878

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001394114.1(RBFOX2):c.1184C>T(p.Thr395Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,596,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T395K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

RBFOX2
NM_001394114.1 missense, splice_region

Scores

Splicing: ADA: 0.005829

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.612

Publications

2 publications found

Variant links:

Genes affected

RBFOX2 (HGNC:9906): (RNA binding fox-1 homolog 2) This gene is one of several human genes similar to the C. elegans gene Fox-1. This gene encodes an RNA binding protein that is thought to be a key regulator of alternative exon splicing in the nervous system and other cell types. The protein binds to a conserved UGCAUG element found downstream of many alternatively spliced exons and promotes inclusion of the alternative exon in mature transcripts. The protein also interacts with the estrogen receptor 1 transcription factor and regulates estrogen receptor 1 transcriptional activity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RBFOX2 Gene-Disease associations (from GenCC):

congenital heart defects, multiple types
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
congenital heart disease
Inheritance: AD Classification: STRONG Submitted by: ClinGen

RBFOX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13737771).

BP6

Variant 22-35746475-G-A is Benign according to our data. Variant chr22-35746475-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3943472.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394114.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBFOX2	NM_001349999.2	MANE Select	c.1224C>T	p.Asp408Asp	splice_region synonymous	Exon 12 of 14	NP_001336928.2	A0A8Q3WKT3
RBFOX2	NM_001394114.1		c.1184C>T	p.Thr395Met	missense splice_region	Exon 11 of 13	NP_001381043.1
RBFOX2	NM_001394115.1		c.1181C>T	p.Thr394Met	missense splice_region	Exon 11 of 13	NP_001381044.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBFOX2	ENST00000359369.8	TSL:1	c.983C>T	p.Thr328Met	missense splice_region	Exon 12 of 14	ENSP00000352328.4	B0QYY4
RBFOX2	ENST00000414461.6	TSL:1	c.983C>T	p.Thr328Met	missense splice_region	Exon 10 of 12	ENSP00000407855.2	O43251-4
RBFOX2	ENST00000405409.6	TSL:1	c.974C>T	p.Thr325Met	missense splice_region	Exon 10 of 12	ENSP00000384944.2	O43251-9

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000458

AC:

AN:

240094

AF XY:

0.0000461

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.0000837

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000346

AC:

AN:

1444564

Hom.:

Cov.:

AF XY:

0.0000320

AC XY:

AN XY:

719074

show subpopulations

African (AFR)

AF:

0.0000610

AC:

AN:

32804

American (AMR)

AF:

0.0000233

AC:

AN:

42950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25624

East Asian (EAS)

AF:

0.00

AC:

AN:

39222

South Asian (SAS)

AF:

0.00

AC:

AN:

84720

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0000382

AC:

AN:

1100658

Other (OTH)

AF:

0.0000671

AC:

AN:

59648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.0000460

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2088

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

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:

0.0000452

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.061

Eigen_PC

Benign

0.0099

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.82

M_CAP

Benign

0.0076

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

PhyloP100

0.61

PROVEAN

Benign

-1.8

REVEL

Benign

0.058

Sift

Benign

0.14

Sift4G

Uncertain

0.048

Polyphen

0.0010

Vest4

0.39

MVP

0.71

ClinPred

0.035

GERP RS

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0058

dbscSNV1_RF

Benign

0.33

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over