22-35746496-G-A

Variant names:

• chr22-35746496-G-A
• rs142561018
• ENST00000359369.8:c.962C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001394114.1(RBFOX2):​c.1163C>T​(p.Pro388Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,606,406 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RBFOX2 NM_001394114.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.623

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0668776).
• BP6: Variant 22-35746496-G-A is Benign according to our data. Variant chr22-35746496-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3711839.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1203C>T	p.Ala401Ala	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.962C>T	p.Pro321Leu	missense_variant	Exon 10 of 12	1		ENSP00000407855.2
RBFOX2	ENST00000695854.1	c.1203C>T	p.Ala401Ala	synonymous_variant	Exon 12 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1215C>T	p.Ala405Ala	synonymous_variant	Exon 12 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.1002C>T	p.Ala334Ala	synonymous_variant	Exon 11 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000695805.1	n.*496C>T		non_coding_transcript_exon_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4186C>T		non_coding_transcript_exon_variant	Exon 13 of 15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*496C>T		3_prime_UTR_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4186C>T		3_prime_UTR_variant	Exon 13 of 15			ENSP00000512187.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000493 AC: 12 AN: 243222 Hom.: 0 AF XY: 0.0000455 AC XY: 6 AN XY: 131918

Gnomad AFR exome AF: 0.000320

Gnomad AMR exome AF: 0.000149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1454274 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 723696

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74322

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000742 AC: 9

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Uncertain	1.0
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	0.22	N;N;N
REVEL	Benign	0.064
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.58	T;T;D
Polyphen		0.0	B;B;B
Vest4		0.47
MVP		0.40
ClinPred		0.055	T
GERP RS		0.66
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: rs142561018; hg19: chr22-36142543;