rs5750175

Variant names:

• chr22-35753291-G-T
• rs5750175
• NM_001349999.2:c.1137+2814C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001349999.2(RBFOX2):​c.1137+2814C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,104 control chromosomes in the GnomAD database, including 5,369 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 (5369 hom., cov: 32)
• Consequence: RBFOX2 NM_001349999.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 3 publications found

Genes affected

RBFOX2 (HGNC:9906): (RNA binding fox-1 homolog 2) This gene is one of several human genes similar to the C. elegans gene Fox-1. This gene encodes an RNA binding protein that is thought to be a key regulator of alternative exon splicing in the nervous system and other cell types. The protein binds to a conserved UGCAUG element found downstream of many alternatively spliced exons and promotes inclusion of the alternative exon in mature transcripts. The protein also interacts with the estrogen receptor 1 transcription factor and regulates estrogen receptor 1 transcriptional activity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RBFOX2 Gene-Disease associations (from GenCC):

• congenital heart defects, multiple types

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1137+2814C>A		intron_variant	Intron 11 of 13	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.1137+2814C>A		intron_variant	Intron 11 of 13		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1149+2814C>A		intron_variant	Intron 11 of 13	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.936+2814C>A		intron_variant	Intron 10 of 12	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.896+6597C>A		intron_variant	Intron 9 of 11	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*430+6597C>A		intron_variant	Intron 10 of 12			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*389+2814C>A		intron_variant	Intron 11 of 14			ENSP00000512187.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32649 AN: 151986 Hom.: 5332 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0795

Gnomad SAS AF: 0.0986

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.174

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

GnomAD4 genome AF: 0.215 AC: 32744 AN: 152104 Hom.: 5369 Cov.: 32 AF XY: 0.208 AC XY: 15445 AN XY: 74348

African (AFR) AF: 0.461 AC: 19099 AN: 41454

American (AMR) AF: 0.118 AC: 1805 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3470

East Asian (EAS) AF: 0.0799 AC: 414 AN: 5182

South Asian (SAS) AF: 0.0991 AC: 477 AN: 4814

European-Finnish (FIN) AF: 0.0995 AC: 1053 AN: 10586

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8972 AN: 67996

Other (OTH) AF: 0.173 AC: 365 AN: 2114

Alfa AF: 0.157 Hom.: 3059

Bravo AF: 0.228

Asia WGS AF: 0.111 AC: 388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.068
DANN	Benign	0.33
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5750175; hg19: chr22-36149338;