Variant 22-35759892-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001349999.2(RBFOX2):c.1093C>G(p.Pro365Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,362 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: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RBFOX2
NM_001349999.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.77

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21814963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX2	NM_001349999.2 linkuse as main transcript	c.1093C>G	p.Pro365Ala	missense_variant	10/14	ENST00000695854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX2	ENST00000695854.1 linkuse as main transcript	c.1093C>G	p.Pro365Ala	missense_variant	10/14		NM_001349999.2	P3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460362

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726542

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Apr 19, 2023

The c.1105C>G (p.P369A) alteration is located in exon 10 (coding exon 10) of the RBFOX2 gene. This alteration results from a C to G substitution at nucleotide position 1105, causing the proline (P) at amino acid position 369 to be replaced by an alanine (A). 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

0.064

BayesDel_noAF

Benign

-0.15

Cadd

Uncertain

Dann

Benign

0.64

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.21

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

MetaSVM

Benign

-0.49

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.2

N;N;N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0030

D;D;T;T;T;T;T;T

Sift4G

Benign

0.57

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

Polyphen

0.89

P;P;P;D;P;D;D;D

Vest4

0.52

MutPred

0.51

.;.;.;.;.;Gain of catalytic residue at P274 (P = 0.0135);.;.;

MVP

0.19

MPC

2.2

ClinPred

0.83

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over