rs140174146

chr16-7579839-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018723.4(RBFOX1):c.333A>G(p.Glu111=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,614,028 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (12 hom., cov: 32)
  • Exomes 𝑓: 0.012 (160 hom.)
• Consequence: RBFOX1 NM_018723.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.79

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-7579839-A-G is Benign according to our data. Variant chr16-7579839-A-G is described in ClinVar as [Benign]. Clinvar id is 415961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00987 (1502/152228) while in subpopulation SAS AF= 0.0185 (89/4822). AF 95% confidence interval is 0.0154. There are 12 homozygotes in gnomad4. There are 739 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1505 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX1	NM_018723.4	c.333A>G	p.Glu111=	synonymous_variant	6/16	ENST00000550418.6
RBFOX1	NM_145893.3	c.393A>G	p.Glu131=	synonymous_variant	3/14	ENST00000355637.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX1	ENST00000550418.6	c.333A>G	p.Glu111=	synonymous_variant	6/16	1	NM_018723.4	A1
RBFOX1	ENST00000355637.9	c.393A>G	p.Glu131=	synonymous_variant	3/14	1	NM_145893.3

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 1505 AN: 152110 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.0131 AC: 3278 AN: 251056 Hom.: 47 AF XY: 0.0142 AC XY: 1924 AN XY: 135662

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.0481

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0205

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0118 AC: 17254 AN: 1461800 Hom.: 160 Cov.: 31 AF XY: 0.0122 AC XY: 8879 AN XY: 727200

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.0459

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0214

Gnomad4 FIN exome AF: 0.0174

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.00987 AC: 1502 AN: 152228 Hom.: 12 Cov.: 32 AF XY: 0.00993 AC XY: 739 AN XY: 74442

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00805

Gnomad4 ASJ AF: 0.0438

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0185

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0136 Hom.: 9

Bravo AF: 0.00813

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 05, 2017

- -

Idiopathic generalized epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.0
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs140174146; hg19: chr16-7629841; COSMIC: COSV60980684; COSMIC: COSV60980684;