NM_018723.4:c.1071+3G>A

Variant names:

• chr16-7709134-G-A
• rs79369633
• NM_018723.4:c.1071+3G>A

Variant summary

Our verdict is Benign. The variant received -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 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.0004631
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.33
• Publications: 4 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

ENSG00000301273 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 241954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2668 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.1071+3G>A		splice_region_variant, intron_variant	Intron 15 of 15	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.1187+3G>A		splice_region_variant, intron_variant	Intron 13 of 13	ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.1071+3G>A		splice_region_variant, intron_variant	Intron 15 of 15	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.1187+3G>A		splice_region_variant, intron_variant	Intron 13 of 13	1	NM_145893.3	ENSP00000347855.4

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

GnomAD2 exomes AF: 0.0205 AC: 5135 AN: 250658 AF XY: 0.0225

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 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

African (AFR) AF: 0.00377 AC: 126 AN: 33418

American (AMR) AF: 0.00892 AC: 398 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 474 AN: 26124

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39620

South Asian (SAS) AF: 0.0294 AC: 2529 AN: 86068

European-Finnish (FIN) AF: 0.0353 AC: 1886 AN: 53406

Middle Eastern (MID) AF: 0.0363 AC: 209 AN: 5760

European-Non Finnish (NFE) AF: 0.0262 AC: 29035 AN: 1109188

Other (OTH) AF: 0.0225 AC: 1358 AN: 60294

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

African (AFR) AF: 0.00366 AC: 152 AN: 41540

American (AMR) AF: 0.00994 AC: 152 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0274 AC: 132 AN: 4820

European-Finnish (FIN) AF: 0.0407 AC: 431 AN: 10596

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0248 AC: 1689 AN: 68014

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.0219 Hom.: 60

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

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RBFOX1-related disorder Benign:1

May 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Idiopathic generalized epilepsy Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.81
PhyloP100		2.3
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs79369633; hg19: chr16-7759136;