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

6
11

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]

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
RBFOX2NM_001349999.2 linkc.1192G>A p.Ala398Thr missense_variant 12/14 ENST00000695854.1 NP_001336928.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RBFOX2ENST00000695854.1 linkc.1192G>A p.Ala398Thr missense_variant 12/14 NM_001349999.2 ENSP00000512219.1 A0A8Q3WKT3
RBFOX2ENST00000438146.7 linkc.1204G>A p.Ala402Thr missense_variant 12/141 ENSP00000413035.2 O43251-8
RBFOX2ENST00000449924.6 linkc.991G>A p.Ala331Thr missense_variant 11/131 ENSP00000391670.2 O43251-10
RBFOX2ENST00000414461.6 linkc.951G>A p.Pro317Pro synonymous_variant 10/121 ENSP00000407855.2 O43251-4
RBFOX2ENST00000695805.1 linkn.*485G>A non_coding_transcript_exon_variant 11/13 ENSP00000512185.1 A0A8Q3SI20
RBFOX2ENST00000695807.1 linkn.*4175G>A non_coding_transcript_exon_variant 13/15 ENSP00000512187.1 A0A8Q3SI31
RBFOX2ENST00000695805.1 linkn.*485G>A 3_prime_UTR_variant 11/13 ENSP00000512185.1 A0A8Q3SI20
RBFOX2ENST00000695807.1 linkn.*4175G>A 3_prime_UTR_variant 13/15 ENSP00000512187.1 A0A8Q3SI31

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152178
Hom.:
0
Cov.:
32
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:
7
AN:
244550
Hom.:
0
AF XY:
0.0000226
AC XY:
3
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:
99
AN:
1457222
Hom.:
0
Cov.:
30
AF XY:
0.0000759
AC XY:
55
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:
2
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
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.:
0
Bravo
AF:
0.0000227
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

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 submitterclinical testingAmbry GeneticsDec 07, 2024The 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
T
BayesDel_noAF
Benign
-0.27
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.021
.;.;T;.;.
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D;D;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.31
T;T;T;T;T
MetaSVM
Benign
-0.82
T
PrimateAI
Uncertain
0.68
T
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
T
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.

Other links and lift over

dbSNP: rs760198924; hg19: chr22-36142554; API