22-35759892-G-C

Variant names:

• chr22-35759892-G-C
• NM_001349999.2:c.1093C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001349999.2(RBFOX2):​c.1093C>G​(p.Pro365Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RBFOX2 NM_001349999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21814963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1093C>G	p.Pro365Ala	missense_variant	Exon 10 of 14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.1093C>G	p.Pro365Ala	missense_variant	Exon 10 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1105C>G	p.Pro369Ala	missense_variant	Exon 10 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.892C>G	p.Pro298Ala	missense_variant	Exon 9 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.892C>G	p.Pro298Ala	missense_variant	Exon 9 of 12	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*426C>G		non_coding_transcript_exon_variant	Exon 10 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*345C>G		non_coding_transcript_exon_variant	Exon 10 of 15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*426C>G		3_prime_UTR_variant	Exon 10 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*345C>G		3_prime_UTR_variant	Exon 10 of 15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460362 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726542

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1105C>G (p.P369A) alteration is located in exon 10 (coding exon 10) of the RBFOX2 gene. This alteration results from a C to G substitution at nucleotide position 1105, causing the proline (P) at amino acid position 369 to be replaced by an alanine (A). 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	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.64
DEOGEN2	Benign	0.030	.;.;.;.;T;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D;D;T;T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T;T;T;T
Polyphen		0.89	P;P;P;D;P;D;D;D
Vest4		0.52
MutPred		0.51		.;.;.;.;.;Gain of catalytic residue at P274 (P = 0.0135);.;.;
MVP		0.19
MPC		2.2
ClinPred		0.83	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-36155939;