17-79096683-A-C

Variant names:

• chr17-79096683-A-C
• NM_001350451.2:c.906T>G
• RBFOX3 p.Tyr302*

Variant summary

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

The NM_001350451.2(RBFOX3):​c.906T>G​(p.Tyr302*) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBFOX3 NM_001350451.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 0 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, NO_KNOWN Submitted by: ClinGen, Ambry Genetics

ACMG classification

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

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	NM_001350451.2	MANE Select	c.906T>G	p.Tyr302*	stop_gained	Exon 12 of 15	NP_001337380.1	A0A8I5KWJ3
	RBFOX3	NM_001385804.1		c.906T>G	p.Tyr302*	stop_gained	Exon 12 of 15	NP_001372733.1
	RBFOX3	NM_001385805.1		c.906T>G	p.Tyr302*	stop_gained	Exon 13 of 16	NP_001372734.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	ENST00000693108.1	MANE Select	c.906T>G	p.Tyr302*	stop_gained	Exon 12 of 15	ENSP00000510395.1	A0A8I5KWJ3
	RBFOX3	ENST00000857749.1		c.1002T>G	p.Tyr334*	stop_gained	Exon 12 of 15	ENSP00000527808.1
	RBFOX3	ENST00000583458.5	TSL:5	c.903T>G	p.Tyr301*	stop_gained	Exon 11 of 14	ENSP00000464186.1	J3QRF4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		1.9
PromoterAI		0.027	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-77092765;