rs1555902810

Variant names:

• chr22-35781685-G-GA
• rs1555902810
• NM_001349999.2:c.523dupT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001349999.2(RBFOX2):​c.523dupT​(p.Ser175PhefsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBFOX2 NM_001349999.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.416
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-35781685-G-GA is Pathogenic according to our data. Variant chr22-35781685-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 521760.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.523dupT	p.Ser175PhefsTer4	frameshift_variant	Exon 4 of 14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.523dupT	p.Ser175PhefsTer4	frameshift_variant	Exon 4 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.523dupT	p.Ser175PhefsTer4	frameshift_variant	Exon 4 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.310dupT	p.Ser104PhefsTer4	frameshift_variant	Exon 3 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.310dupT	p.Ser104PhefsTer4	frameshift_variant	Exon 3 of 12	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.313dupT		non_coding_transcript_exon_variant	Exon 3 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.253dupT		non_coding_transcript_exon_variant	Exon 4 of 15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jun 05, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1555902810; hg19: chr22-36177732;