chr16-6241018-G-C

Variant names:

• chr16-6241018-G-C
• rs13336322
• NM_018723.4:c.-126-75977G>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.-126-75977G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 151,896 control chromosomes in the GnomAD database, including 4,859 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 0.22 (4859 hom., cov: 32)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.928
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018723.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	NM_018723.4	MANE Select	c.-126-75977G>C		intron	N/A	NP_061193.2
	RBFOX1	NM_001415887.1		c.472-75977G>C		intron	N/A	NP_001402816.1
	RBFOX1	NM_001415888.1		c.472-75977G>C		intron	N/A	NP_001402817.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	ENST00000550418.6	TSL:1 MANE Select	c.-126-75977G>C		intron	N/A	ENSP00000450031.1
	RBFOX1	ENST00000553186.5	TSL:1	c.-126-75977G>C		intron	N/A	ENSP00000447753.1
	RBFOX1	ENST00000547605.5	TSL:1	c.-126-75977G>C		intron	N/A	ENSP00000450402.1

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33861 AN: 151780 Hom.: 4833 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.236

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

GnomAD4 genome AF: 0.223 AC: 33936 AN: 151896 Hom.: 4859 Cov.: 32 AF XY: 0.225 AC XY: 16678 AN XY: 74260

African (AFR) AF: 0.408 AC: 16900 AN: 41400

American (AMR) AF: 0.205 AC: 3123 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 751 AN: 3472

East Asian (EAS) AF: 0.191 AC: 984 AN: 5164

South Asian (SAS) AF: 0.212 AC: 1021 AN: 4806

European-Finnish (FIN) AF: 0.123 AC: 1290 AN: 10522

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9190 AN: 67962

Other (OTH) AF: 0.236 AC: 496 AN: 2102

Alfa AF: 0.0570 Hom.: 61

Bravo AF: 0.234

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.29
DANN	Benign	0.46
PhyloP100		-0.93
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: rs13336322; hg19: chr16-6291019;