Genetic Variant RBFOX3:p.Tyr10* (chr17-79115686-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001350451.2(RBFOX3):c.30C>A(p.Tyr10*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000324 in 308,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y10Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

RBFOX3
NM_001350451.2 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.870

Publications

0 publications found

Variant links:

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

RBFOX3 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBFOX3	NM_001350451.2	MANE Select	c.30C>A	p.Tyr10*	stop_gained	Exon 5 of 15	NP_001337380.1	A0A8I5KWJ3
RBFOX3	NM_001385804.1		c.30C>A	p.Tyr10*	stop_gained	Exon 5 of 15	NP_001372733.1
RBFOX3	NM_001385805.1		c.30C>A	p.Tyr10*	stop_gained	Exon 6 of 16	NP_001372734.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBFOX3	ENST00000693108.1	MANE Select	c.30C>A	p.Tyr10*	stop_gained	Exon 5 of 15	ENSP00000510395.1	A0A8I5KWJ3
RBFOX3	ENST00000857749.1		c.30C>A	p.Tyr10*	stop_gained	Exon 5 of 15	ENSP00000527808.1
RBFOX3	ENST00000583458.5	TSL:5	c.30C>A	p.Tyr10*	stop_gained	Exon 4 of 14	ENSP00000464186.1	J3QRF4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000324

AC:

AN:

308506

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

167940

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

7202

American (AMR)

AF:

0.00

AC:

AN:

15440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8476

East Asian (EAS)

AF:

0.00

AC:

AN:

14156

South Asian (SAS)

AF:

0.00

AC:

AN:

44380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1306

European-Non Finnish (NFE)

AF:

0.00000539

AC:

AN:

185544

Other (OTH)

AF:

0.00

AC:

AN:

15526

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.84

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

PhyloP100

0.87

Vest4

0.19

GERP RS

3.3

PromoterAI

0.039

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over