22-35746518-G-A

Variant names:

• chr22-35746518-G-A
• NM_001349999.2:c.1181C>T

Variant summary

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

The NM_001349999.2(RBFOX2):​c.1181C>T​(p.Thr394Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RBFOX2 NM_001349999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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=0.19955143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1181C>T	p.Thr394Ile	missense_variant	Exon 12 of 14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.1181C>T	p.Thr394Ile	missense_variant	Exon 12 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1193C>T	p.Thr398Ile	missense_variant	Exon 12 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.980C>T	p.Thr327Ile	missense_variant	Exon 11 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.940C>T	p.Pro314Ser	missense_variant	Exon 10 of 12	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*474C>T		non_coding_transcript_exon_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4164C>T		non_coding_transcript_exon_variant	Exon 13 of 15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*474C>T		3_prime_UTR_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4164C>T		3_prime_UTR_variant	Exon 13 of 15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 398 of the RBFOX2 protein (p.Thr398Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RBFOX2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.36	T
PROVEAN	Benign	0.67	N;N;N
REVEL	Benign	0.070
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.27	T;T;T
Polyphen		0.030	B;B;B
Vest4		0.49
MutPred		0.16		.;Loss of loop (P = 0.0603);Loss of loop (P = 0.0603);
MVP		0.43
ClinPred		0.86	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-36142565;