22-35745928-C-A

Variant names:

• chr22-35745928-C-A
• rs563359777
• NM_001349999.2:c.1294G>T

Variant summary

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

The NM_001349999.2(RBFOX2):​c.1294G>T​(p.Ala432Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,520 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A432T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RBFOX2 NM_001349999.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.07
• 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_001349999.2. 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.1294G>T	p.Ala432Ser	missense	Exon 13 of 14	NP_001336928.2	A0A8Q3WKT3
	RBFOX2	NM_001082578.4		c.1306G>T	p.Ala436Ser	missense	Exon 13 of 14	NP_001076047.2	O43251-8
	RBFOX2	NM_001082579.3		c.1303G>T	p.Ala435Ser	missense	Exon 13 of 14	NP_001076048.2	O43251-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX2	ENST00000695854.1	MANE Select	c.1294G>T	p.Ala432Ser	missense	Exon 13 of 14	ENSP00000512219.1	A0A8Q3WKT3
	RBFOX2	ENST00000438146.7	TSL:1	c.1306G>T	p.Ala436Ser	missense	Exon 13 of 14	ENSP00000413035.2	O43251-8
	RBFOX2	ENST00000449924.6	TSL:1	c.1093G>T	p.Ala365Ser	missense	Exon 12 of 13	ENSP00000391670.2	O43251-10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251308 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460520 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726644

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110758

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.23	T
PhyloP100		6.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.72
MutPred		0.44		Gain of glycosylation at A342 (P = 0.0142)
MVP		0.41
MPC		2.1
ClinPred		0.82	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
gMVP		0.71
Mutation Taster		=67/33	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: rs563359777; hg19: chr22-36141975;