chr22-35943950-A-T

Variant names:

• chr22-35943950-A-T
• rs5750203
• NM_001349999.2:c.187-5053T>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.187-5053T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,198 control chromosomes in the GnomAD database, including 5,774 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 (5774 hom., cov: 32)
• Consequence: RBFOX2 NM_001349999.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 2 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.187-5053T>A		intron_variant	Intron 1 of 13	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.187-5053T>A		intron_variant	Intron 1 of 13		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.187-5053T>A		intron_variant	Intron 1 of 13	1		ENSP00000413035.2
RBFOX2	ENST00000695807.1	n.-84-5053T>A		intron_variant	Intron 1 of 14			ENSP00000512187.1
RBFOX2	ENST00000408983.2	c.43-5053T>A		intron_variant	Intron 1 of 5	3		ENSP00000386177.2

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33530 AN: 152080 Hom.: 5739 Cov.: 32

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.0788

Gnomad SAS AF: 0.0981

Gnomad FIN AF: 0.0999

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.221 AC: 33622 AN: 152198 Hom.: 5774 Cov.: 32 AF XY: 0.214 AC XY: 15911 AN XY: 74428

African (AFR) AF: 0.482 AC: 19996 AN: 41468

American (AMR) AF: 0.124 AC: 1900 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3470

East Asian (EAS) AF: 0.0790 AC: 409 AN: 5176

South Asian (SAS) AF: 0.0986 AC: 476 AN: 4828

European-Finnish (FIN) AF: 0.0999 AC: 1061 AN: 10618

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8824 AN: 68020

Other (OTH) AF: 0.184 AC: 389 AN: 2116

Alfa AF: 0.0852 Hom.: 148

Bravo AF: 0.236

Asia WGS AF: 0.110 AC: 383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.030
DANN	Benign	0.72
PhyloP100		-2.4
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: rs5750203; hg19: chr22-36339998;