chr22-35746507-C-T

Position:

chr22-35746507-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001349999.2(RBFOX2):c.1192G>A(p.Ala398Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000628 in 1,609,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

RBFOX2
NM_001349999.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.34

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31216213).

BS2

High AC in GnomAdExome4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX2	NM_001349999.2 link	c.1192G>A	p.Ala398Thr	missense_variant	12/14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RBFOX2	ENST00000695854.1 link	c.1192G>A	p.Ala398Thr	missense_variant	12/14		NM_001349999.2	ENSP00000512219.1	A0A8Q3WKT3
RBFOX2	ENST00000438146.7 link	c.1204G>A	p.Ala402Thr	missense_variant	12/14	1		ENSP00000413035.2	O43251-8
RBFOX2	ENST00000449924.6 link	c.991G>A	p.Ala331Thr	missense_variant	11/13	1		ENSP00000391670.2	O43251-10
RBFOX2	ENST00000414461.6 link	c.951G>A	p.Pro317Pro	synonymous_variant	10/12	1		ENSP00000407855.2	O43251-4
RBFOX2	ENST00000695805.1 link	n.*485G>A		non_coding_transcript_exon_variant	11/13			ENSP00000512185.1	A0A8Q3SI20
RBFOX2	ENST00000695807.1 link	n.*4175G>A		non_coding_transcript_exon_variant	13/15			ENSP00000512187.1	A0A8Q3SI31
RBFOX2	ENST00000695805.1 link	n.*485G>A		3_prime_UTR_variant	11/13			ENSP00000512185.1	A0A8Q3SI20
RBFOX2	ENST00000695807.1 link	n.*4175G>A		3_prime_UTR_variant	13/15			ENSP00000512187.1	A0A8Q3SI31

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000286

AC:

AN:

244550

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132574

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000662

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000458

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000679

AC:

AN:

1457222

Hom.:

Cov.:

AF XY:

0.0000759

AC XY:

AN XY:

725048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000350

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000829

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2024

The c.1204G>A (p.A402T) alteration is located in exon 12 (coding exon 12) of the RBFOX2 gene. This alteration results from a G to A substitution at nucleotide position 1204, causing the alanine (A) at amino acid position 402 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

.;.;T;.;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.31

T;T;T;T;T

MetaSVM

Benign

-0.82

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.72

N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.052

T;D;D;D;D

Sift4G

Benign

0.11

T;T;D;T;T

Polyphen

0.0060

B;B;B;B;B

Vest4

0.57

MutPred

0.40

.;.;Gain of glycosylation at A308 (P = 0.0017);.;.;

MVP

0.34

MPC

1.0

ClinPred

0.16

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over