NM_018723.4:c.-64+50875A>G

Variant names:

• chr16-6367932-A-G
• rs12446308
• NM_018723.4:c.-64+50875A>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.-64+50875A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0891 in 152,162 control chromosomes in the GnomAD database, including 789 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 0.089 (789 hom., cov: 32)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.421
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.-64+50875A>G		intron_variant	Intron 2 of 15	ENST00000550418.6	NP_061193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.-64+50875A>G		intron_variant	Intron 2 of 15	1	NM_018723.4	ENSP00000450031.1

Frequencies

GnomAD3 genomes AF: 0.0892 AC: 13566 AN: 152042 Hom.: 790 Cov.: 32

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.0896

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0756

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.124

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

GnomAD4 genome AF: 0.0891 AC: 13558 AN: 152162 Hom.: 789 Cov.: 32 AF XY: 0.0886 AC XY: 6590 AN XY: 74378

African (AFR) AF: 0.0332 AC: 1377 AN: 41520

American (AMR) AF: 0.0894 AC: 1367 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 701 AN: 3470

East Asian (EAS) AF: 0.0434 AC: 224 AN: 5162

South Asian (SAS) AF: 0.138 AC: 666 AN: 4818

European-Finnish (FIN) AF: 0.0756 AC: 801 AN: 10590

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7977 AN: 68000

Other (OTH) AF: 0.121 AC: 256 AN: 2112

Alfa AF: 0.102 Hom.: 370

Bravo AF: 0.0866

Asia WGS AF: 0.0970 AC: 340 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.59
DANN	Benign	0.41
PhyloP100		-0.42
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: rs12446308; hg19: chr16-6417933;