22-35746517-G-A

Variant names:

• chr22-35746517-G-A
• rs949919887
• ENST00000359369.8:c.941C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001394114.1(RBFOX2):​c.1142C>T​(p.Pro381Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,458,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P381S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RBFOX2 NM_001394114.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.952

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11935747).
• BP6: Variant 22-35746517-G-A is Benign according to our data. Variant chr22-35746517-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3431063.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1182C>T	p.Thr394Thr	synonymous_variant	Exon 12 of 14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000414461.6	c.941C>T	p.Pro314Leu	missense_variant	Exon 10 of 12	1		ENSP00000407855.2
RBFOX2	ENST00000695854.1	c.1182C>T	p.Thr394Thr	synonymous_variant	Exon 12 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1194C>T	p.Thr398Thr	synonymous_variant	Exon 12 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.981C>T	p.Thr327Thr	synonymous_variant	Exon 11 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000695805.1	n.*475C>T		non_coding_transcript_exon_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4165C>T		non_coding_transcript_exon_variant	Exon 13 of 15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*475C>T		3_prime_UTR_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4165C>T		3_prime_UTR_variant	Exon 13 of 15			ENSP00000512187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245502 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133016

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: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1458106 Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11 AN XY: 725442

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 09, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.10
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.050	T;D;D
Polyphen		0.46	P;B;B
Vest4		0.32
MutPred		0.19		.;Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP		0.58
ClinPred		0.18	T
GERP RS		3.0
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

LitVar

Other links and lift over

dbSNP: rs949919887; hg19: chr22-36142564;