NM_018723.4:c.220G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018723.4(RBFOX1):​c.220G>A​(p.Glu74Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E74Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RBFOX1
NM_018723.4 missense

Scores

6
7
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.27

Publications

0 publications found
Variant links:
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]
RBFOX1 Gene-Disease associations (from GenCC):
  • epilepsy
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • neurodevelopmental disorder
    Inheritance: AD Classification: LIMITED Submitted by: G2P
  • autism susceptibility 1
    Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBFOX1NM_018723.4 linkc.220G>A p.Glu74Lys missense_variant Exon 5 of 16 ENST00000550418.6 NP_061193.2 Q9NWB1-1Q59HD3
RBFOX1NM_145893.3 linkc.280G>A p.Glu94Lys missense_variant Exon 2 of 14 ENST00000355637.9 NP_665900.1 Q9NWB1-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBFOX1ENST00000550418.6 linkc.220G>A p.Glu74Lys missense_variant Exon 5 of 16 1 NM_018723.4 ENSP00000450031.1 Q9NWB1-1
RBFOX1ENST00000355637.9 linkc.280G>A p.Glu94Lys missense_variant Exon 2 of 14 1 NM_145893.3 ENSP00000347855.4 Q9NWB1-5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461436
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727020
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44658
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86138
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111792
Other (OTH)
AF:
0.00
AC:
0
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.18
.;.;.;T;.;T;.;.;.;T;.;.;.;.;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.069
D
MetaRNN
Uncertain
0.51
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.78
T
MutationAssessor
Uncertain
2.3
.;.;M;M;.;.;.;.;.;M;.;.;.;.;.;.
PhyloP100
9.3
PrimateAI
Pathogenic
0.79
T
PROVEAN
Uncertain
-2.7
.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
REVEL
Benign
0.26
Sift
Uncertain
0.027
.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
Sift4G
Benign
0.23
.;T;T;T;D;T;D;T;T;T;T;T;T;T;T;T
Polyphen
0.99, 0.99, 1.0, 1.0, 0.97, 1.0
.;.;D;D;D;D;D;.;.;D;D;D;D;.;.;.
Vest4
0.74, 0.77, 0.81, 0.79, 0.84, 0.82, 0.75, 0.81, 0.78, 0.84, 0.81, 0.86
MutPred
0.26
.;.;.;.;Gain of methylation at E117 (P = 0.0026);Gain of methylation at E117 (P = 0.0026);.;.;.;.;.;.;.;.;.;.;
MVP
0.24
MPC
0.016
ClinPred
0.99
D
GERP RS
4.7
Varity_R
0.75
gMVP
0.60
Mutation Taster
=29/71
disease causing

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

Other links and lift over

dbSNP: rs748804086; hg19: chr16-7568341; COSMIC: COSV100299358; API