22-35745985-C-T

Variant names:

• chr22-35745985-C-T
• rs764357200
• NM_001349999.2:c.1237G>A

Variant summary

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

The NM_001349999.2(RBFOX2):​c.1237G>A​(p.Val413Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,264 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 6.07

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]

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 rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1237G>A	p.Val413Met	missense_variant	Exon 13 of 14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.1237G>A	p.Val413Met	missense_variant	Exon 13 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1249G>A	p.Val417Met	missense_variant	Exon 13 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.1036G>A	p.Val346Met	missense_variant	Exon 12 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.996G>A	p.Gly332Gly	synonymous_variant	Exon 11 of 12	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*530G>A		non_coding_transcript_exon_variant	Exon 12 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4220G>A		non_coding_transcript_exon_variant	Exon 14 of 15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*530G>A		3_prime_UTR_variant	Exon 12 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4220G>A		3_prime_UTR_variant	Exon 14 of 15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251154 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135740

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461264 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727002

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1249G>A (p.V417M) alteration is located in exon 13 (coding exon 13) of the RBFOX2 gene. This alteration results from a G to A substitution at nucleotide position 1249, causing the valine (V) at amino acid position 417 to be replaced by a methionine (M). 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	0.13	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	.;.;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.74
MutPred		0.33		.;.;Gain of disorder (P = 0.0652);.;.;
MVP		0.60
MPC		2.2
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs764357200; hg19: chr22-36142032;