chr22-35746491-G-A

Position:

• chr22-35746491-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001394114.1(RBFOX2):​c.1168C>T​(p.Gln390*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000689 in 1,452,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RBFOX2 NM_001394114.1 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1208C>T	p.Ala403Val	missense_variant	12/14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000414461.6	c.967C>T	p.Gln323*	stop_gained	10/12	1		ENSP00000407855.2
RBFOX2	ENST00000695854.1	c.1208C>T	p.Ala403Val	missense_variant	12/14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1220C>T	p.Ala407Val	missense_variant	12/14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.1007C>T	p.Ala336Val	missense_variant	11/13	1		ENSP00000391670.2
RBFOX2	ENST00000695805.1	n.*501C>T		non_coding_transcript_exon_variant	11/13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4191C>T		non_coding_transcript_exon_variant	13/15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*501C>T		3_prime_UTR_variant	11/13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4191C>T		3_prime_UTR_variant	13/15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452190 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722700

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: 0.00

Gnomad4 OTH exome AF: 0.0000167

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

Jun 05, 2024

The c.1220C>T (p.A407V) alteration is located in exon 12 (coding exon 12) of the RBFOX2 gene. This alteration results from a C to T substitution at nucleotide position 1220, causing the alanine (A) at amino acid position 407 to be replaced by a valine (V). 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	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	.;.;T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Benign	-0.51	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0080	D;D;D;D;D
Sift4G	Uncertain	0.048	D;T;D;D;T
Polyphen		0.81	P;B;P;B;P
Vest4		0.68
MutPred		0.50		.;.;Loss of disorder (P = 0.0362);.;.;
MVP		0.26
MPC		1.9
ClinPred		0.93	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.85

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: rs1932807659; hg19: chr22-36142538;