rs4786847

Variant names:

• chr16-6260232-G-A
• rs4786847
• NM_018723.4:c.-126-56763G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018723.4(RBFOX1):​c.-126-56763G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 151,980 control chromosomes in the GnomAD database, including 40,875 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 0.69 (40875 hom., cov: 32)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.847
• Publications: 10 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.-126-56763G>A		intron_variant	Intron 1 of 15	ENST00000550418.6	NP_061193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.-126-56763G>A		intron_variant	Intron 1 of 15	1	NM_018723.4	ENSP00000450031.1

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105136 AN: 151862 Hom.: 40868 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.888

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.703

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

GnomAD4 genome AF: 0.692 AC: 105161 AN: 151980 Hom.: 40875 Cov.: 32 AF XY: 0.692 AC XY: 51446 AN XY: 74318

African (AFR) AF: 0.307 AC: 12695 AN: 41364

American (AMR) AF: 0.736 AC: 11241 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 2688 AN: 3466

East Asian (EAS) AF: 0.822 AC: 4229 AN: 5142

South Asian (SAS) AF: 0.745 AC: 3589 AN: 4818

European-Finnish (FIN) AF: 0.888 AC: 9401 AN: 10590

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.865 AC: 58835 AN: 68006

Other (OTH) AF: 0.702 AC: 1482 AN: 2110

Alfa AF: 0.808 Hom.: 42294

Bravo AF: 0.664

Asia WGS AF: 0.741 AC: 2577 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	0.052
DANN	Benign	0.73
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4786847; hg19: chr16-6310233;