22-35756129-G-A

Variant summary

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

The NM_001349999.2(RBFOX2):c.1113C>T(p.Asp371=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000719 in 1,501,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: RBFOX2 NM_001349999.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.19

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 (BayesDel_noAF=-0.45).
• BP6: Variant 22-35756129-G-A is Benign according to our data. Variant chr22-35756129-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 750495.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX2	NM_001349999.2	c.1113C>T	p.Asp371=	synonymous_variant	11/14	ENST00000695854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX2	ENST00000695854.1	c.1113C>T	p.Asp371=	synonymous_variant	11/14		NM_001349999.2	P3

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000489 AC: 7 AN: 143112 Hom.: 0 AF XY: 0.0000393 AC XY: 3 AN XY: 76390

Gnomad AFR exome AF: 0.000150

Gnomad AMR exome AF: 0.0000463

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: 0.0000851

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000734 AC: 99 AN: 1349100 Hom.: 0 Cov.: 30 AF XY: 0.0000736 AC XY: 49 AN XY: 665750

Gnomad4 AFR exome AF: 0.0000672

Gnomad4 AMR exome AF: 0.0000302

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000300

Gnomad4 SAS exome AF: 0.0000140

Gnomad4 FIN exome AF: 0.0000417

Gnomad4 NFE exome AF: 0.0000877

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74278

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000389 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	19
Dann	Benign	0.67
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: rs779612165; hg19: chr22-36152176; COSMIC: COSV99455918; COSMIC: COSV99455918;