17-79094526-G-T

Variant names:

• chr17-79094526-G-T
• rs972548690
• NM_001350451.2:c.1002C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001350451.2(RBFOX3):​c.1002C>A​(p.Tyr334*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y334Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBFOX3 NM_001350451.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.169
• Publications: 1 publications found

Genes affected

RBFOX3 (HGNC:27097): (RNA binding fox-1 homolog 3) This gene encodes a member of the RNA-binding FOX protein family which is involved in the regulation of alternative splicing of pre-mRNA. The protein has an N-terminal proline-rich region, an RNA recognition motif (RRM) domain, and a C-terminal alanine-rich region. This gene produces the neuronal nuclei (NeuN) antigen that has been widely used as a marker for post-mitotic neurons. This gene has its highest expression in the central nervous system and plays a prominent role in neural tissue development and regulation of adult brain function. Mutations in this gene have been associated with numerous neurological disorders. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2017]

RBFOX3 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-79094526-G-T is Pathogenic according to our data. Variant chr17-79094526-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 433136.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350451.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	NM_001350451.2	MANE Select	c.1002C>A	p.Tyr334*	stop_gained	Exon 14 of 15	NP_001337380.1
	RBFOX3	NM_001385804.1		c.1002C>A	p.Tyr334*	stop_gained	Exon 14 of 15	NP_001372733.1
	RBFOX3	NM_001385805.1		c.1002C>A	p.Tyr334*	stop_gained	Exon 15 of 16	NP_001372734.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	ENST00000693108.1	MANE Select	c.1002C>A	p.Tyr334*	stop_gained	Exon 14 of 15	ENSP00000510395.1
	RBFOX3	ENST00000583458.5	TSL:5	c.999C>A	p.Tyr333*	stop_gained	Exon 13 of 14	ENSP00000464186.1
	RBFOX3	ENST00000582043.5	TSL:5	c.909C>A	p.Tyr303*	stop_gained	Exon 10 of 11	ENSP00000463964.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1001718 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 485260

African (AFR) AF: 0.00 AC: 0 AN: 16900

American (AMR) AF: 0.00 AC: 0 AN: 7390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12774

East Asian (EAS) AF: 0.00 AC: 0 AN: 6684

South Asian (SAS) AF: 0.00 AC: 0 AN: 58730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837568

Other (OTH) AF: 0.00 AC: 0 AN: 36000

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Self-limited epilepsy with centrotemporal spikes Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

CAADphred>15

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	0.10
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.59	D
PhyloP100		-0.17
Vest4		0.44
GERP RS		-2.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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

dbSNP: rs972548690; hg19: chr17-77090608;