16-6851512-T-C

Variant names:

• chr16-6851512-T-C
• rs4129044
• NM_018723.4:c.-16+196862T>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.-16+196862T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 152,070 control chromosomes in the GnomAD database, including 6,863 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 (6863 hom., cov: 32)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61
• Publications: 4 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.-16+196862T>C		intron_variant	Intron 3 of 15	ENST00000550418.6	NP_061193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.-16+196862T>C		intron_variant	Intron 3 of 15	1	NM_018723.4	ENSP00000450031.1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44689 AN: 151948 Hom.: 6852 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.299

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

GnomAD4 genome AF: 0.294 AC: 44719 AN: 152070 Hom.: 6863 Cov.: 32 AF XY: 0.291 AC XY: 21627 AN XY: 74344

African (AFR) AF: 0.223 AC: 9256 AN: 41486

American (AMR) AF: 0.272 AC: 4157 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1202 AN: 3472

East Asian (EAS) AF: 0.378 AC: 1959 AN: 5176

South Asian (SAS) AF: 0.381 AC: 1832 AN: 4812

European-Finnish (FIN) AF: 0.233 AC: 2463 AN: 10578

Middle Eastern (MID) AF: 0.371 AC: 104 AN: 280

European-Non Finnish (NFE) AF: 0.337 AC: 22913 AN: 67976

Other (OTH) AF: 0.304 AC: 639 AN: 2102

Alfa AF: 0.322 Hom.: 12748

Bravo AF: 0.294

Asia WGS AF: 0.363 AC: 1263 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.9
DANN	Benign	0.75
PhyloP100		1.6
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: rs4129044; hg19: chr16-6901513;