22-35746474-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001349999.2(RBFOX2):​c.1225G>T​(p.Gly409Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000152 in 1,444,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G409S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RBFOX2
NM_001349999.2 missense, splice_region

Scores

4
9
4
Splicing: ADA: 0.9933
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.01
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BS2
High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBFOX2NM_001349999.2 linkc.1225G>T p.Gly409Cys missense_variant, splice_region_variant Exon 12 of 14 ENST00000695854.1 NP_001336928.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBFOX2ENST00000695854.1 linkc.1225G>T p.Gly409Cys missense_variant, splice_region_variant Exon 12 of 14 NM_001349999.2 ENSP00000512219.1 A0A8Q3WKT3
RBFOX2ENST00000438146.7 linkc.1237G>T p.Gly413Cys missense_variant, splice_region_variant Exon 12 of 14 1 ENSP00000413035.2 O43251-8
RBFOX2ENST00000449924.6 linkc.1024G>T p.Gly342Cys missense_variant, splice_region_variant Exon 11 of 13 1 ENSP00000391670.2 O43251-10
RBFOX2ENST00000414461.6 linkc.984G>T p.Thr328Thr splice_region_variant, synonymous_variant Exon 10 of 12 1 ENSP00000407855.2 O43251-4
RBFOX2ENST00000695805.1 linkn.*518G>T splice_region_variant, non_coding_transcript_exon_variant Exon 11 of 13 ENSP00000512185.1 A0A8Q3SI20
RBFOX2ENST00000695807.1 linkn.*4208G>T splice_region_variant, non_coding_transcript_exon_variant Exon 13 of 15 ENSP00000512187.1 A0A8Q3SI31
RBFOX2ENST00000695805.1 linkn.*518G>T 3_prime_UTR_variant Exon 11 of 13 ENSP00000512185.1 A0A8Q3SI20
RBFOX2ENST00000695807.1 linkn.*4208G>T 3_prime_UTR_variant Exon 13 of 15 ENSP00000512187.1 A0A8Q3SI31

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000152
AC:
22
AN:
1444060
Hom.:
0
Cov.:
30
AF XY:
0.0000181
AC XY:
13
AN XY:
718760
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:
0.0000191
Gnomad4 OTH exome
AF:
0.0000168
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jan 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 413 of the RBFOX2 protein (p.Gly413Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RBFOX2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Benign
0.030
.;.;T;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.87
D;D;D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D
MetaSVM
Uncertain
-0.27
T
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-2.2
N;N;N;N;D
REVEL
Benign
0.21
Sift
Uncertain
0.0060
D;D;D;D;D
Sift4G
Uncertain
0.018
D;D;D;D;D
Polyphen
0.99
D;D;D;D;D
Vest4
0.87
MutPred
0.64
.;.;Loss of disorder (P = 0.0325);.;.;
MVP
0.47
MPC
2.2
ClinPred
0.97
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.78
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.

Other links and lift over

dbSNP: rs370030634; hg19: chr22-36142521; API