16-6060546-C-T

Variant names:

• chr16-6060546-C-T
• rs1035564
• NM_018723.4:c.-127+40554C>T

Variant summary

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

The NM_018723.4(RBFOX1):​c.-127+40554C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 151,940 control chromosomes in the GnomAD database, including 23,080 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 0.54 (23080 hom., cov: 31)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.136
• Publications: 10 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

ENSG00000257180 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.-127+40554C>T		intron_variant	Intron 1 of 15	ENST00000550418.6	NP_061193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.-127+40554C>T		intron_variant	Intron 1 of 15	1	NM_018723.4	ENSP00000450031.1

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82765 AN: 151822 Hom.: 23081 Cov.: 31

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.545

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

GnomAD4 genome AF: 0.545 AC: 82797 AN: 151940 Hom.: 23080 Cov.: 31 AF XY: 0.542 AC XY: 40268 AN XY: 74252

African (AFR) AF: 0.417 AC: 17284 AN: 41404

American (AMR) AF: 0.571 AC: 8714 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1875 AN: 3470

East Asian (EAS) AF: 0.584 AC: 3005 AN: 5146

South Asian (SAS) AF: 0.543 AC: 2619 AN: 4820

European-Finnish (FIN) AF: 0.566 AC: 5979 AN: 10558

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41374 AN: 67962

Other (OTH) AF: 0.546 AC: 1150 AN: 2108

Alfa AF: 0.589 Hom.: 116374

Bravo AF: 0.542

Asia WGS AF: 0.531 AC: 1850 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.61
PhyloP100		-0.14
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: rs1035564; hg19: chr16-6110547;