22-35745973-C-T

Variant names:

• chr22-35745973-C-T
• rs771797500
• NM_001349999.2:c.1249G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001349999.2(RBFOX2):​c.1249G>A​(p.Asp417Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RBFOX2 NM_001349999.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1249G>A	p.Asp417Asn	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.1249G>A	p.Asp417Asn	missense_variant	Exon 13 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1261G>A	p.Asp421Asn	missense_variant	Exon 13 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.1048G>A	p.Asp350Asn	missense_variant	Exon 12 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.1008G>A	p.Pro336Pro	synonymous_variant	Exon 11 of 12	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*542G>A		non_coding_transcript_exon_variant	Exon 12 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4232G>A		non_coding_transcript_exon_variant	Exon 14 of 15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*542G>A		3_prime_UTR_variant	Exon 12 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4232G>A		3_prime_UTR_variant	Exon 14 of 15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251302 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135832

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461676 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727160

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1261G>A (p.D421N) 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 1261, causing the aspartic acid (D) at amino acid position 421 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 421 of the RBFOX2 protein (p.Asp421Asn). This variant is present in population databases (rs771797500, gnomAD 0.0009%). 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	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	.;.;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Uncertain	-0.0096	T
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.84
MutPred		0.45		.;.;Loss of phosphorylation at Y329 (P = 0.0778);.;.;
MVP		0.55
MPC		2.2
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.90

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: rs771797500; hg19: chr22-36142020; COSMIC: COSV53266844;