Genetic Variant RBFOX1:c.757+1093T>C (chr16-7631776-T-C) – 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.757+1093T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 151,988 control chromosomes in the GnomAD database, including 9,928 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 0.36 ( 9928 hom., cov: 32)

Consequence

RBFOX1
NM_018723.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.883

Publications

8 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=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4 link	c.757+1093T>C		intron_variant	Intron 11 of 15	ENST00000550418.6	NP_061193.2	Q9NWB1-1Q59HD3
RBFOX1	NM_145893.3 link	c.817+1093T>C		intron_variant	Intron 8 of 13	ENST00000355637.9	NP_665900.1	Q9NWB1-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6 link	c.757+1093T>C		intron_variant	Intron 11 of 15	1	NM_018723.4	ENSP00000450031.1		Q9NWB1-1
RBFOX1	ENST00000355637.9 link	c.817+1093T>C		intron_variant	Intron 8 of 13	1	NM_145893.3	ENSP00000347855.4		Q9NWB1-5

Frequencies

GnomAD3 genomes

AF:

0.356

AC:

54058

AN:

151870

Hom.:

9912

Cov.:

show subpopulations

Gnomad AFR

AF:

0.365

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.364

Gnomad ASJ

AF:

0.344

Gnomad EAS

AF:

0.685

Gnomad SAS

AF:

0.287

Gnomad FIN

AF:

0.300

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.390

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

GnomAD4 genome

AF:

0.356

AC:

54111

AN:

151988

Hom.:

9928

Cov.:

AF XY:

0.355

AC XY:

26343

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.365

AC:

15113

AN:

41454

American (AMR)

AF:

0.364

AC:

5560

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.344

AC:

1196

AN:

3472

East Asian (EAS)

AF:

0.685

AC:

3531

AN:

5154

South Asian (SAS)

AF:

0.288

AC:

1387

AN:

4816

European-Finnish (FIN)

AF:

0.300

AC:

3175

AN:

10566

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.337

AC:

22877

AN:

67942

Other (OTH)

AF:

0.392

AC:

825

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1775

3550

5326

7101

8876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.345

Hom.:

38569

Bravo

AF:

0.365

Asia WGS

AF:

0.449

AC:

1561

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.50

(source)

DANN

Benign

0.75

PhyloP100

-0.88

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