16-5472389-C-G

Variant names:

• chr16-5472389-C-G
• rs3859163
• ENST00000641259.1:c.258+5135C>G

Variant summary

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

The ENST00000641259.1(RBFOX1):​c.258+5135C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 151,978 control chromosomes in the GnomAD database, including 5,941 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 0.27 (5941 hom., cov: 31)
• Consequence: RBFOX1 ENST00000641259.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• Publications: 0 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_001415887.1	c.378+5135C>G		intron_variant	Intron 2 of 19		NP_001402816.1
RBFOX1	NM_001415888.1	c.378+5135C>G		intron_variant	Intron 2 of 17		NP_001402817.1
RBFOX1	XM_017023318.3	c.378+5135C>G		intron_variant	Intron 2 of 19		XP_016878807.1
RBFOX1	XM_024450303.2	c.340-126513C>G		intron_variant	Intron 1 of 18		XP_024306071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000641259.1	c.258+5135C>G		intron_variant	Intron 2 of 19			ENSP00000493041.1
RBFOX1	ENST00000585867.2	c.258+5135C>G		intron_variant	Intron 2 of 2	2		ENSP00000493140.1
RBFOX1	ENST00000569895.3	n.343+5135C>G		intron_variant	Intron 2 of 6	3

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41641 AN: 151860 Hom.: 5927 Cov.: 31

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.270

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

GnomAD4 genome AF: 0.274 AC: 41689 AN: 151978 Hom.: 5941 Cov.: 31 AF XY: 0.274 AC XY: 20323 AN XY: 74270

African (AFR) AF: 0.346 AC: 14328 AN: 41436

American (AMR) AF: 0.281 AC: 4296 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 731 AN: 3472

East Asian (EAS) AF: 0.319 AC: 1641 AN: 5140

South Asian (SAS) AF: 0.165 AC: 793 AN: 4808

European-Finnish (FIN) AF: 0.235 AC: 2477 AN: 10554

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16760 AN: 67974

Other (OTH) AF: 0.266 AC: 561 AN: 2108

Alfa AF: 0.152 Hom.: 278

Bravo AF: 0.284

Asia WGS AF: 0.218 AC: 757 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.8
DANN	Benign	0.53
PhyloP100		0.063

Splicing

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

Other links and lift over

dbSNP: rs3859163; hg19: chr16-5522390;