chr22-35756109-A-G

Variant names:

• chr22-35756109-A-G
• NM_001349999.2:c.1133T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001349999.2(RBFOX2):​c.1133T>C​(p.Leu378Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBFOX2 NM_001349999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.04
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital heart defects, multiple types

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1133T>C	p.Leu378Pro	missense_variant	Exon 11 of 14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.1133T>C	p.Leu378Pro	missense_variant	Exon 11 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1145T>C	p.Leu382Pro	missense_variant	Exon 11 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.932T>C	p.Leu311Pro	missense_variant	Exon 10 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000695807.1	n.*385T>C		non_coding_transcript_exon_variant	Exon 11 of 15			ENSP00000512187.1
RBFOX2	ENST00000695807.1	n.*385T>C		3_prime_UTR_variant	Exon 11 of 15			ENSP00000512187.1
RBFOX2	ENST00000414461.6	c.896+3779T>C		intron_variant	Intron 9 of 11	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*430+3779T>C		intron_variant	Intron 10 of 12			ENSP00000512185.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1316628 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 648756

African (AFR) AF: 0.00 AC: 0 AN: 28616

American (AMR) AF: 0.00 AC: 0 AN: 30782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23168

East Asian (EAS) AF: 0.00 AC: 0 AN: 31862

South Asian (SAS) AF: 0.00 AC: 0 AN: 65226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5374

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1031388

Other (OTH) AF: 0.00 AC: 0 AN: 53588

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with RBFOX2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 382 of the RBFOX2 protein (p.Leu382Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	.;.;T;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T;T;T;D;T;T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
PhyloP100		8.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.1	D;D;D;N;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.0010	B;D;B;D;B;D
Vest4		0.85
MutPred		0.55		.;.;.;Loss of stability (P = 0.0485);.;.;
MVP		0.56
MPC		1.6
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.93
Mutation Taster		=34/66	disease causing

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

Other links and lift over

hg19: chr22-36152156;