16-7275637-A-C

Variant names:

• chr16-7275637-A-C
• rs12445208
• NM_018723.4:c.27+223539A>C

Variant summary

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

The NM_018723.4(RBFOX1):​c.27+223539A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 150,774 control chromosomes in the GnomAD database, including 1,667 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 0.13 (1667 hom., cov: 32)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.444
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.27+223539A>C		intron_variant	Intron 4 of 15	ENST00000550418.6	NP_061193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.27+223539A>C		intron_variant	Intron 4 of 15	1	NM_018723.4	ENSP00000450031.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20120 AN: 150656 Hom.: 1668 Cov.: 32

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.0920

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.273

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.163

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

GnomAD4 genome AF: 0.133 AC: 20122 AN: 150774 Hom.: 1667 Cov.: 32 AF XY: 0.130 AC XY: 9564 AN XY: 73702

African (AFR) AF: 0.0497 AC: 2061 AN: 41442

American (AMR) AF: 0.126 AC: 1896 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 432 AN: 3324

East Asian (EAS) AF: 0.00483 AC: 25 AN: 5176

South Asian (SAS) AF: 0.0933 AC: 450 AN: 4822

European-Finnish (FIN) AF: 0.165 AC: 1732 AN: 10498

Middle Eastern (MID) AF: 0.283 AC: 81 AN: 286

European-Non Finnish (NFE) AF: 0.192 AC: 12906 AN: 67140

Other (OTH) AF: 0.162 AC: 337 AN: 2084

Alfa AF: 0.170 Hom.: 10379

Bravo AF: 0.125

Asia WGS AF: 0.0440 AC: 154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.9
DANN	Benign	0.71
PhyloP100		0.44
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: rs12445208; hg19: chr16-7325638;