22-35745947-G-A
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2
The NM_001394114.1(RBFOX2):c.1235C>T(p.Pro412Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000582 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
RBFOX2
NM_001394114.1 missense
NM_001394114.1 missense
Scores
1
4
10
Clinical Significance
Conservation
PhyloP100: 4.30
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.22687677).
BP6
Variant 22-35745947-G-A is Benign according to our data. Variant chr22-35745947-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3152112.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RBFOX2 | NM_001349999.2 | c.1275C>T | p.Ala425Ala | synonymous_variant | 13/14 | ENST00000695854.1 | NP_001336928.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBFOX2 | ENST00000414461.6 | c.1034C>T | p.Pro345Leu | missense_variant | 11/12 | 1 | ENSP00000407855.2 | |||
RBFOX2 | ENST00000695854.1 | c.1275C>T | p.Ala425Ala | synonymous_variant | 13/14 | NM_001349999.2 | ENSP00000512219.1 | |||
RBFOX2 | ENST00000438146.7 | c.1287C>T | p.Ala429Ala | synonymous_variant | 13/14 | 1 | ENSP00000413035.2 | |||
RBFOX2 | ENST00000449924.6 | c.1074C>T | p.Ala358Ala | synonymous_variant | 12/13 | 1 | ENSP00000391670.2 | |||
RBFOX2 | ENST00000695805.1 | n.*568C>T | non_coding_transcript_exon_variant | 12/13 | ENSP00000512185.1 | |||||
RBFOX2 | ENST00000695807.1 | n.*4258C>T | non_coding_transcript_exon_variant | 14/15 | ENSP00000512187.1 | |||||
RBFOX2 | ENST00000695805.1 | n.*568C>T | 3_prime_UTR_variant | 12/13 | ENSP00000512185.1 | |||||
RBFOX2 | ENST00000695807.1 | n.*4258C>T | 3_prime_UTR_variant | 14/15 | ENSP00000512187.1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251348Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135846
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GnomAD4 exome AF: 0.0000595 AC: 87AN: 1461702Hom.: 0 Cov.: 30 AF XY: 0.0000701 AC XY: 51AN XY: 727172
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74334
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Pathogenic
D;D;D
Sift4G
Benign
T;T;D
Polyphen
B;B;B
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at