NM_018723.4:c.757+1093T>C

Variant names:

• chr16-7631776-T-C
• rs758491
• NM_018723.4:c.757+1093T>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.757+1093T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 151,988 control chromosomes in the GnomAD database, including 9,928 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 0.36 (9928 hom., cov: 32)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.883
• Publications: 8 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.757+1093T>C		intron_variant	Intron 11 of 15	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.817+1093T>C		intron_variant	Intron 8 of 13	ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.757+1093T>C		intron_variant	Intron 11 of 15	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.817+1093T>C		intron_variant	Intron 8 of 13	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54058 AN: 151870 Hom.: 9912 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.390

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

GnomAD4 genome AF: 0.356 AC: 54111 AN: 151988 Hom.: 9928 Cov.: 32 AF XY: 0.355 AC XY: 26343 AN XY: 74272

African (AFR) AF: 0.365 AC: 15113 AN: 41454

American (AMR) AF: 0.364 AC: 5560 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1196 AN: 3472

East Asian (EAS) AF: 0.685 AC: 3531 AN: 5154

South Asian (SAS) AF: 0.288 AC: 1387 AN: 4816

European-Finnish (FIN) AF: 0.300 AC: 3175 AN: 10566

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22877 AN: 67942

Other (OTH) AF: 0.392 AC: 825 AN: 2104

Alfa AF: 0.345 Hom.: 38569

Bravo AF: 0.365

Asia WGS AF: 0.449 AC: 1561 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.50
DANN	Benign	0.75
PhyloP100		-0.88
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: rs758491; hg19: chr16-7681778;