rs113298071
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_018723.4(RBFOX1):c.137C>A(p.Pro46His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,614,146 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0031 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00030 ( 5 hom. )
Consequence
RBFOX1
NM_018723.4 missense
NM_018723.4 missense
Scores
1
9
8
Clinical Significance
Conservation
PhyloP100: 7.31
Genes affected
RBFOX1 (HGNC:18222): (RNA binding fox-1 homolog 1) The Fox-1 family of RNA-binding proteins is evolutionarily conserved, and regulates tissue-specific alternative splicing in metazoa. Fox-1 recognizes a (U)GCAUG stretch in regulated exons or in flanking introns. The protein binds to the C-terminus of ataxin-2 and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the product of the SCA2 gene which causes familial neurodegenerative diseases. Fox-1 and ataxin-2 are both localized in the trans-Golgi network. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.00788638).
BP6
Variant 16-7518256-C-A is Benign according to our data. Variant chr16-7518256-C-A is described in ClinVar as [Benign]. Clinvar id is 415956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7518256-C-A is described in Lovd as [Likely_benign]. Variant chr16-7518256-C-A is described in Lovd as [Benign].
BS2
High AC in GnomAd4 at 478 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RBFOX1 | NM_018723.4 | c.137C>A | p.Pro46His | missense_variant | 5/16 | ENST00000550418.6 | NP_061193.2 | |
RBFOX1 | NM_145893.3 | c.197C>A | p.Pro66His | missense_variant | 2/14 | ENST00000355637.9 | NP_665900.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBFOX1 | ENST00000550418.6 | c.137C>A | p.Pro46His | missense_variant | 5/16 | 1 | NM_018723.4 | ENSP00000450031 | A1 | |
RBFOX1 | ENST00000355637.9 | c.197C>A | p.Pro66His | missense_variant | 2/14 | 1 | NM_145893.3 | ENSP00000347855 |
Frequencies
GnomAD3 genomes AF: 0.00313 AC: 476AN: 152170Hom.: 4 Cov.: 32
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GnomAD3 exomes AF: 0.000816 AC: 205AN: 251348Hom.: 0 AF XY: 0.000560 AC XY: 76AN XY: 135834
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GnomAD4 exome AF: 0.000300 AC: 438AN: 1461858Hom.: 5 Cov.: 31 AF XY: 0.000243 AC XY: 177AN XY: 727234
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GnomAD4 genome AF: 0.00314 AC: 478AN: 152288Hom.: 4 Cov.: 32 AF XY: 0.00308 AC XY: 229AN XY: 74462
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:1
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Idiopathic generalized epilepsy Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;.;T;.;T;.;.;.;T;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;D;T;D;D;D;D;D;D;D;D;D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;M;M;.;.;.;.;.;M;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
REVEL
Benign
Sift
Uncertain
.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
Sift4G
Uncertain
.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.0070, 1.0, 1.0
.;.;B;D;D;D;D;.;.;D;D;D;D;.;.;.
Vest4
0.67, 0.77, 0.74, 0.71, 0.64, 0.75, 0.73, 0.72, 0.77, 0.68, 0.68
MVP
0.13
MPC
0.016
ClinPred
T
GERP RS
Varity_R
gMVP
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