rs79369633

Positions:

• chr16-7709134-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_018723.4(RBFOX1):​c.1071+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,610,716 control chromosomes in the GnomAD database, including 602 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (31 hom., cov: 31)
  • Exomes 𝑓: 0.025 (571 hom.)
• Consequence: RBFOX1 NM_018723.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0004631
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.33

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 16-7709134-G-A is Benign according to our data. Variant chr16-7709134-G-A is described in ClinVar as [Benign]. Clinvar id is 241954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7709134-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0175 (2668/152208) while in subpopulation SAS AF= 0.0274 (132/4820). AF 95% confidence interval is 0.0238. There are 31 homozygotes in gnomad4. There are 1361 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2668 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.1071+3G>A		splice_donor_region_variant, intron_variant		ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.1187+3G>A		splice_donor_region_variant, intron_variant		ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000355637.9	c.1187+3G>A		splice_donor_region_variant, intron_variant		1	NM_145893.3	ENSP00000347855
RBFOX1	ENST00000550418.6	c.1071+3G>A		splice_donor_region_variant, intron_variant		1	NM_018723.4	ENSP00000450031	A1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2672 AN: 152090 Hom.: 31 Cov.: 31

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00996

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0276

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0205 AC: 5135 AN: 250658 Hom.: 92 AF XY: 0.0225 AC XY: 3042 AN XY: 135446

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00870

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0288

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0246

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0247 AC: 36017 AN: 1458508 Hom.: 571 Cov.: 31 AF XY: 0.0251 AC XY: 18198 AN XY: 725726

Gnomad4 AFR exome AF: 0.00377

Gnomad4 AMR exome AF: 0.00892

Gnomad4 ASJ exome AF: 0.0181

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0294

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0225

GnomAD4 genome AF: 0.0175 AC: 2668 AN: 152208 Hom.: 31 Cov.: 31 AF XY: 0.0183 AC XY: 1361 AN XY: 74422

Gnomad4 AFR AF: 0.00366

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0274

Gnomad4 FIN AF: 0.0407

Gnomad4 NFE AF: 0.0248

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0214 Hom.: 21

Bravo AF: 0.0149

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0262

EpiControl AF: 0.0265

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 12, 2017

- -

RBFOX1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Idiopathic generalized epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs79369633; hg19: chr16-7759136;