Genetic Variant RBFOX3:c.-175+10038A>G (chr17-79472416-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001350451.2(RBFOX3):c.-175+10038A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,158 control chromosomes in the GnomAD database, including 1,992 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 1992 hom., cov: 32)

Consequence

RBFOX3
NM_001350451.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.15

Publications

20 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
RBFOX3	NM_001350451.2	MANE Select	c.-175+10038A>G	intron	N/A	NP_001337380.1	A0A8I5KWJ3
RBFOX3	NM_001385804.1		c.-175+10038A>G	intron	N/A	NP_001372733.1
RBFOX3	NM_001385805.1		c.-175+10038A>G	intron	N/A	NP_001372734.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RBFOX3	ENST00000693108.1	MANE Select	c.-175+10038A>G	intron	N/A	ENSP00000510395.1	A0A8I5KWJ3
RBFOX3	ENST00000857749.1		c.-175+10038A>G	intron	N/A	ENSP00000527808.1
RBFOX3	ENST00000583458.5	TSL:5	c.-175+10038A>G	intron	N/A	ENSP00000464186.1	J3QRF4

Frequencies

GnomAD3 genomes

AF:

0.158

AC:

23993

AN:

152040

Hom.:

1993

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.215

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.162

Gnomad SAS

AF:

0.141

Gnomad FIN

AF:

0.207

Gnomad MID

AF:

0.239

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.158

AC:

24003

AN:

152158

Hom.:

1992

Cov.:

AF XY:

0.158

AC XY:

11736

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.120

AC:

4999

AN:

41514

American (AMR)

AF:

0.153

AC:

2339

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

740

AN:

3472

East Asian (EAS)

AF:

0.162

AC:

840

AN:

5188

South Asian (SAS)

AF:

0.140

AC:

674

AN:

4816

European-Finnish (FIN)

AF:

0.207

AC:

2190

AN:

10582

Middle Eastern (MID)

AF:

0.233

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.170

AC:

11575

AN:

67984

Other (OTH)

AF:

0.181

AC:

382

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1042

2085

3127

4170

5212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

260

520

780

1040

1300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.165

Hom.:

3158

Bravo

AF:

0.155

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.35

(source)

DANN

Benign

0.34

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism

(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