22-35746474-C-T

Variant names:

• chr22-35746474-C-T
• rs370030634
• NM_001349999.2:c.1225G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001349999.2(RBFOX2):​c.1225G>A​(p.Gly409Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000138 in 1,444,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G409C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RBFOX2 NM_001349999.2 missense, splice_region
• Scores: Splicing: ADA: 0.001135
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23970982).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1225G>A	p.Gly409Ser	missense_variant, splice_region_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.1225G>A	p.Gly409Ser	missense_variant, splice_region_variant	Exon 12 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1237G>A	p.Gly413Ser	missense_variant, splice_region_variant	Exon 12 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.1024G>A	p.Gly342Ser	missense_variant, splice_region_variant	Exon 11 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.984G>A	p.Thr328Thr	splice_region_variant, synonymous_variant	Exon 10 of 12	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*518G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4208G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*518G>A		3_prime_UTR_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4208G>A		3_prime_UTR_variant	Exon 13 of 15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000167 AC: 4 AN: 239732 Hom.: 0 AF XY: 0.0000154 AC XY: 2 AN XY: 129862

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1444060 Hom.: 0 Cov.: 30 AF XY: 0.00000974 AC XY: 7 AN XY: 718760

Gnomad4 AFR exome AF: 0.0000610

Gnomad4 AMR exome AF: 0.0000466

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000764

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.00000818

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 413 of the RBFOX2 protein (p.Gly413Ser). This variant is present in population databases (rs370030634, gnomAD 0.007%). 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 tolerated. 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	-0.11	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Benign	0.37
DEOGEN2	Benign	0.0022	.;.;T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	1.1	N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.92	T;T;T;T;T
Polyphen		0.026	B;B;B;B;B
Vest4		0.61
MVP		0.50
MPC		1.1
ClinPred		0.073	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.070
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: rs370030634; hg19: chr22-36142521;