rs4581716

Variant names:

• chr16-7408134-A-G
• rs4581716
• NM_018723.4:c.28-110013A>G

Variant summary

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

The NM_018723.4(RBFOX1):​c.28-110013A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,144 control chromosomes in the GnomAD database, including 8,060 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 0.31 (8060 hom., cov: 33)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.28-110013A>G		intron_variant	Intron 4 of 15	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.87+75046A>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	c.28-110013A>G		intron_variant	Intron 4 of 15	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.87+75046A>G		intron_variant	Intron 1 of 13	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47830 AN: 152026 Hom.: 8063 Cov.: 33

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.0728

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.356

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

GnomAD4 genome AF: 0.315 AC: 47855 AN: 152144 Hom.: 8060 Cov.: 33 AF XY: 0.306 AC XY: 22730 AN XY: 74382

African (AFR) AF: 0.243 AC: 10078 AN: 41512

American (AMR) AF: 0.315 AC: 4812 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1365 AN: 3468

East Asian (EAS) AF: 0.0728 AC: 377 AN: 5178

South Asian (SAS) AF: 0.288 AC: 1389 AN: 4826

European-Finnish (FIN) AF: 0.271 AC: 2869 AN: 10590

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.380 AC: 25820 AN: 67976

Other (OTH) AF: 0.358 AC: 753 AN: 2106

Alfa AF: 0.362 Hom.: 15367

Bravo AF: 0.315

Asia WGS AF: 0.193 AC: 672 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.0
DANN	Benign	0.60
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4581716; hg19: chr16-7458135;