16-6846127-A-G

Variant names:

• chr16-6846127-A-G
• rs11645781
• NM_018723.4:c.-16+191477A>G

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+191477A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 152,126 control chromosomes in the GnomAD database, including 43,938 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 0.76 (43938 hom., cov: 33)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.688
• Publications: 2 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.-16+191477A>G		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+191477A>G		intron_variant	Intron 3 of 15	1	NM_018723.4	ENSP00000450031.1

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114988 AN: 152008 Hom.: 43890 Cov.: 33

Gnomad AFR AF: 0.844

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.724

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

GnomAD4 genome AF: 0.757 AC: 115099 AN: 152126 Hom.: 43938 Cov.: 33 AF XY: 0.754 AC XY: 56071 AN XY: 74360

African (AFR) AF: 0.844 AC: 35003 AN: 41496

American (AMR) AF: 0.780 AC: 11926 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 2249 AN: 3468

East Asian (EAS) AF: 0.886 AC: 4587 AN: 5180

South Asian (SAS) AF: 0.794 AC: 3827 AN: 4818

European-Finnish (FIN) AF: 0.628 AC: 6638 AN: 10564

Middle Eastern (MID) AF: 0.699 AC: 204 AN: 292

European-Non Finnish (NFE) AF: 0.715 AC: 48628 AN: 67996

Other (OTH) AF: 0.725 AC: 1531 AN: 2112

Alfa AF: 0.733 Hom.: 58379

Bravo AF: 0.772

Asia WGS AF: 0.843 AC: 2935 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.20
DANN	Benign	0.34
PhyloP100		-0.69
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: rs11645781; hg19: chr16-6896128;