chr22-35745947-G-T

Variant names:

• chr22-35745947-G-T
• rs367628350
• ENST00000359369.8:c.1034C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001394114.1(RBFOX2):​c.1235C>A​(p.Pro412Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P412L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBFOX2 NM_001394114.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30
• 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
• congenital heart disease

  Inheritance: AD Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394114.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX2	NM_001349999.2	MANE Select	c.1275C>A	p.Ala425Ala	synonymous	Exon 13 of 14	NP_001336928.2	A0A8Q3WKT3
	RBFOX2	NM_001394114.1		c.1235C>A	p.Pro412Gln	missense	Exon 12 of 13	NP_001381043.1
	RBFOX2	NM_001394115.1		c.1232C>A	p.Pro411Gln	missense	Exon 12 of 13	NP_001381044.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX2	ENST00000359369.8	TSL:1	c.1034C>A	p.Pro345Gln	missense	Exon 13 of 14	ENSP00000352328.4	B0QYY4
	RBFOX2	ENST00000414461.6	TSL:1	c.1034C>A	p.Pro345Gln	missense	Exon 11 of 12	ENSP00000407855.2	O43251-4
	RBFOX2	ENST00000405409.6	TSL:1	c.1025C>A	p.Pro342Gln	missense	Exon 11 of 12	ENSP00000384944.2	O43251-9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.87	T
PhyloP100		4.3
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.078	T
Polyphen		0.99	D
Vest4		0.64
MutPred		0.33		Loss of loop (P = 0.0031)
MVP		0.66
ClinPred		0.87	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=74/26	polymorphism

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: rs367628350; hg19: chr22-36141994;