16-7653811-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018723.4(RBFOX1):​c.758-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,607,664 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 12 hom., cov: 33)
Exomes 𝑓: 0.00071 ( 18 hom. )

Consequence

RBFOX1
NM_018723.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0005488
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.59
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
Variant 16-7653811-G-T is Benign according to our data. Variant chr16-7653811-G-T is described in ClinVar as [Benign]. Clinvar id is 415963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00615 (934/151974) while in subpopulation AFR AF= 0.0216 (896/41466). AF 95% confidence interval is 0.0204. There are 12 homozygotes in gnomad4. There are 436 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 934 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RBFOX1NM_018723.4 linkc.758-4G>T splice_region_variant, intron_variant ENST00000550418.6 NP_061193.2 Q9NWB1-1Q59HD3
RBFOX1NM_145893.3 linkc.818-4G>T splice_region_variant, intron_variant ENST00000355637.9 NP_665900.1 Q9NWB1-5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RBFOX1ENST00000550418.6 linkc.758-4G>T splice_region_variant, intron_variant 1 NM_018723.4 ENSP00000450031.1 Q9NWB1-1
RBFOX1ENST00000355637.9 linkc.818-4G>T splice_region_variant, intron_variant 1 NM_145893.3 ENSP00000347855.4 Q9NWB1-5

Frequencies

GnomAD3 genomes
AF:
0.00610
AC:
926
AN:
151858
Hom.:
11
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0215
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00151
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:
0.0000883
Gnomad OTH
AF:
0.00431
GnomAD3 exomes
AF:
0.00162
AC:
376
AN:
231890
Hom.:
8
AF XY:
0.00113
AC XY:
145
AN XY:
128162
show subpopulations
Gnomad AFR exome
AF:
0.0244
Gnomad AMR exome
AF:
0.000879
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000881
Gnomad OTH exome
AF:
0.000518
GnomAD4 exome
AF:
0.000706
AC:
1028
AN:
1455690
Hom.:
18
Cov.:
36
AF XY:
0.000565
AC XY:
409
AN XY:
724432
show subpopulations
Gnomad4 AFR exome
AF:
0.0255
Gnomad4 AMR exome
AF:
0.000940
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00189
GnomAD4 genome
AF:
0.00615
AC:
934
AN:
151974
Hom.:
12
Cov.:
33
AF XY:
0.00587
AC XY:
436
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.0216
Gnomad4 AMR
AF:
0.00150
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000883
Gnomad4 OTH
AF:
0.00427
Alfa
AF:
0.00135
Hom.:
0
Bravo
AF:
0.00697
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMar 19, 2021- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Idiopathic generalized epilepsy Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.17
DANN
Benign
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00055
dbscSNV1_RF
Benign
0.016
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: rs112339093; hg19: chr16-7703813; API