chr16-5451935-A-C

Variant names:

• chr16-5451935-A-C
• rs538835
• ENST00000641259.1:c.220-15281A>C

Variant summary

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

The NM_001415887.1(RBFOX1):​c.340-15281A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 151,860 control chromosomes in the GnomAD database, including 6,268 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 0.25 (6268 hom., cov: 31)
• Consequence: RBFOX1 NM_001415887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.416
• Publications: 3 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001415887.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	NM_001415887.1		c.340-15281A>C		intron	N/A	NP_001402816.1
	RBFOX1	NM_001415888.1		c.340-15281A>C		intron	N/A	NP_001402817.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	ENST00000641259.1		c.220-15281A>C		intron	N/A	ENSP00000493041.1
	RBFOX1	ENST00000585867.2	TSL:2	c.220-15281A>C		intron	N/A	ENSP00000493140.1
	RBFOX1	ENST00000569895.3	TSL:3	n.305-15281A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38230 AN: 151742 Hom.: 6264 Cov.: 31

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.0789

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.234

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

GnomAD4 genome AF: 0.252 AC: 38265 AN: 151860 Hom.: 6268 Cov.: 31 AF XY: 0.249 AC XY: 18461 AN XY: 74228

African (AFR) AF: 0.470 AC: 19436 AN: 41336

American (AMR) AF: 0.223 AC: 3396 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 733 AN: 3466

East Asian (EAS) AF: 0.0789 AC: 406 AN: 5148

South Asian (SAS) AF: 0.185 AC: 892 AN: 4812

European-Finnish (FIN) AF: 0.172 AC: 1817 AN: 10576

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.160 AC: 10873 AN: 67952

Other (OTH) AF: 0.231 AC: 487 AN: 2112

Alfa AF: 0.191 Hom.: 2442

Bravo AF: 0.265

Asia WGS AF: 0.143 AC: 497 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.8
DANN	Benign	0.45
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs538835; hg19: chr16-5501936; COSMIC: COSV73936827;