22-35746475-G-T

Position:

chr22-35746475-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001349999.2(RBFOX2):c.1224C>A(p.Asp408Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,596,738 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

RBFOX2
NM_001349999.2 missense, splice_region

Scores

Splicing: ADA: 0.00006175

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.612

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:

RBFOX2 (HGNC:):

RBFOX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX2	NM_001349999.2 linkuse as main transcript	c.1224C>A	p.Asp408Glu	missense_variant, splice_region_variant	12/14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RBFOX2	ENST00000695854.1 linkuse as main transcript	c.1224C>A	p.Asp408Glu	missense_variant, splice_region_variant	12/14		NM_001349999.2	ENSP00000512219.1	A0A8Q3WKT3
RBFOX2	ENST00000438146.7 linkuse as main transcript	c.1236C>A	p.Asp412Glu	missense_variant, splice_region_variant	12/14	1		ENSP00000413035.2	O43251-8
RBFOX2	ENST00000449924.6 linkuse as main transcript	c.1023C>A	p.Asp341Glu	missense_variant, splice_region_variant	11/13	1		ENSP00000391670.2	O43251-10
RBFOX2	ENST00000414461.6 linkuse as main transcript	c.983C>A	p.Thr328Lys	missense_variant, splice_region_variant	10/12	1		ENSP00000407855.2	O43251-4
RBFOX2	ENST00000695805.1 linkuse as main transcript	n.*517C>A		splice_region_variant, non_coding_transcript_exon_variant	11/13			ENSP00000512185.1	A0A8Q3SI20
RBFOX2	ENST00000695807.1 linkuse as main transcript	n.*4207C>A		splice_region_variant, non_coding_transcript_exon_variant	13/15			ENSP00000512187.1	A0A8Q3SI31
RBFOX2	ENST00000695805.1 linkuse as main transcript	n.*517C>A		3_prime_UTR_variant	11/13			ENSP00000512185.1	A0A8Q3SI20
RBFOX2	ENST00000695807.1 linkuse as main transcript	n.*4207C>A		3_prime_UTR_variant	13/15			ENSP00000512187.1	A0A8Q3SI31

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152172

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1444566

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

719076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000454

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

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

Jan 29, 2024

The c.1236C>A (p.D412E) alteration is located in exon 12 (coding exon 12) of the RBFOX2 gene. This alteration results from a C to A substitution at nucleotide position 1236, causing the aspartic acid (D) at amino acid position 412 to be replaced by a glutamic acid (E). 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

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;.;T;.;.

Eigen

Benign

0.10

Eigen_PC

Benign

0.040

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.61

D;D;D;D;D

MetaSVM

Benign

-1.1

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.0

D;D;D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Benign

0.45

T;T;T;T;T

Polyphen

0.98

D;P;D;P;D

Vest4

0.82

MutPred

0.48

.;.;Loss of phosphorylation at Y320 (P = 0.1101);.;.;

MVP

0.63

MPC

2.1

ClinPred

0.98

GERP RS

0.82

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000062

dbscSNV1_RF

Benign

0.14

SpliceAI score (max)

0.010

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