16-6316989-C-G

Variant names:

• chr16-6316989-C-G
• rs928189351
• NM_018723.4:c.-126-6C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018723.4(RBFOX1):​c.-126-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,380,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RBFOX1 NM_018723.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009353
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0130
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.-126-6C>G		splice_region_variant, 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.-126-6C>G		splice_region_variant, intron_variant	Intron 1 of 15	1	NM_018723.4	ENSP00000450031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1380328 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 681190

African (AFR) AF: 0.00 AC: 0 AN: 31386

American (AMR) AF: 0.00 AC: 0 AN: 35252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25022

East Asian (EAS) AF: 0.00 AC: 0 AN: 35710

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076936

Other (OTH) AF: 0.00 AC: 0 AN: 57724

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		0.013

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000094
dbscSNV1_RF	Benign	0.022

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs928189351; hg19: chr16-6366990;