16-7409346-T-A

Variant names:

• chr16-7409346-T-A
• rs10500355
• NM_018723.4:c.28-108801T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

The NM_018723.4(RBFOX1):​c.28-108801T>A variant causes a intron change. The variant allele was found at a frequency of 0.292 in 152,150 control chromosomes in the GnomAD database, including 7,075 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 0.29 (7075 hom., cov: 33)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76
• Publications: 24 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.13).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.28-108801T>A		intron_variant	Intron 4 of 15	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.87+76258T>A		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.28-108801T>A		intron_variant	Intron 4 of 15	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.87+76258T>A		intron_variant	Intron 1 of 13	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44355 AN: 152032 Hom.: 7076 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.0634

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.319

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

GnomAD4 genome AF: 0.292 AC: 44389 AN: 152150 Hom.: 7075 Cov.: 33 AF XY: 0.285 AC XY: 21198 AN XY: 74372

African (AFR) AF: 0.197 AC: 8166 AN: 41514

American (AMR) AF: 0.293 AC: 4482 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1310 AN: 3472

East Asian (EAS) AF: 0.0634 AC: 328 AN: 5176

South Asian (SAS) AF: 0.246 AC: 1185 AN: 4820

European-Finnish (FIN) AF: 0.269 AC: 2854 AN: 10598

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24960 AN: 67968

Other (OTH) AF: 0.317 AC: 668 AN: 2106

Alfa AF: 0.341 Hom.: 1267

Bravo AF: 0.288

Asia WGS AF: 0.159 AC: 553 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.86
PhyloP100		3.8
Mutation Taster		=99/1	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: rs10500355; hg19: chr16-7459347;