Genetic Variant RBFOX1:c.28-139725C>G (chr16-7378422-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018723.4(RBFOX1):c.28-139725C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 151,918 control chromosomes in the GnomAD database, including 28,130 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.60 ( 28130 hom., cov: 31)

Consequence

RBFOX1
NM_018723.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.57

Publications

4 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

RBFOX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4 link	c.28-139725C>G		intron_variant	Intron 4 of 15	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3 link	c.87+45334C>G		intron_variant	Intron 1 of 13	ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6 link	c.28-139725C>G		intron_variant	Intron 4 of 15	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9 link	c.87+45334C>G		intron_variant	Intron 1 of 13	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes

AF:

0.600

AC:

91038

AN:

151800

Hom.:

28095

Cov.:

show subpopulations

Gnomad AFR

AF:

0.743

Gnomad AMI

AF:

0.520

Gnomad AMR

AF:

0.538

Gnomad ASJ

AF:

0.596

Gnomad EAS

AF:

0.628

Gnomad SAS

AF:

0.627

Gnomad FIN

AF:

0.566

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.531

Gnomad OTH

AF:

0.548

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.600

AC:

91123

AN:

151918

Hom.:

28130

Cov.:

AF XY:

0.601

AC XY:

44622

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.743

AC:

30806

AN:

41450

American (AMR)

AF:

0.537

AC:

8205

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.596

AC:

2067

AN:

3468

East Asian (EAS)

AF:

0.627

AC:

3208

AN:

5116

South Asian (SAS)

AF:

0.627

AC:

3021

AN:

4816

European-Finnish (FIN)

AF:

0.566

AC:

5965

AN:

10538

Middle Eastern (MID)

AF:

0.500

AC:

147

AN:

294

European-Non Finnish (NFE)

AF:

0.531

AC:

36070

AN:

67944

Other (OTH)

AF:

0.551

AC:

1160

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1814

3628

5442

7256

9070

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

760

1520

2280

3040

3800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.425

Hom.:

1119

Bravo

AF:

0.598

Asia WGS

AF:

0.674

AC:

2341

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.0080

(source)

DANN

Benign

0.098

PhyloP100

-2.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over