22-35746492-C-A

Position:

• chr22-35746492-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001349999.2(RBFOX2):​c.1207G>T​(p.Ala403Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000158 in 1,452,418 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: 0.000016 (0 hom.)
• Consequence: RBFOX2 NM_001349999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38910615).
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1207G>T	p.Ala403Ser	missense_variant	12/14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.1207G>T	p.Ala403Ser	missense_variant	12/14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1219G>T	p.Ala407Ser	missense_variant	12/14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.1006G>T	p.Ala336Ser	missense_variant	11/13	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.966G>T	p.Leu322Leu	synonymous_variant	10/12	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*500G>T		non_coding_transcript_exon_variant	11/13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4190G>T		non_coding_transcript_exon_variant	13/15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*500G>T		3_prime_UTR_variant	11/13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4190G>T		3_prime_UTR_variant	13/15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1452418 Hom.: 0 Cov.: 30 AF XY: 0.0000194 AC XY: 14 AN XY: 722766

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: 0.0000199

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 407 of the RBFOX2 protein (p.Ala407Ser). 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	-0.0087	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;.;T;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.81	P;B;P;B;P
Vest4		0.63
MutPred		0.42		.;.;Gain of glycosylation at A313 (P = 0);.;.;
MVP		0.31
MPC		1.8
ClinPred		0.88	D
GERP RS		5.2
gMVP		0.75

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: rs1281377303; hg19: chr22-36142539;