22-35745952-G-A

Position:

• chr22-35745952-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001349999.2(RBFOX2):​c.1270C>T​(p.Pro424Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RBFOX2 NM_001349999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1270C>T	p.Pro424Ser	missense_variant	13/14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.1270C>T	p.Pro424Ser	missense_variant	13/14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1282C>T	p.Pro428Ser	missense_variant	13/14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.1069C>T	p.Pro357Ser	missense_variant	12/13	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.1029C>T	p.Pro343Pro	synonymous_variant	11/12	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*563C>T		non_coding_transcript_exon_variant	12/13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4253C>T		non_coding_transcript_exon_variant	14/15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*563C>T		3_prime_UTR_variant	12/13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4253C>T		3_prime_UTR_variant	14/15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461782 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2023

The c.1282C>T (p.P428S) alteration is located in exon 13 (coding exon 13) of the RBFOX2 gene. This alteration results from a C to T substitution at nucleotide position 1282, causing the proline (P) at amino acid position 428 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	.;.;T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	-0.082	T
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.99	D;P;P;P;D
Vest4		0.95
MutPred		0.61		.;.;Gain of catalytic residue at P334 (P = 0.0191);.;.;
MVP		0.40
MPC		2.1
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs1932528972; hg19: chr22-36141999;