17-79119947-A-G

Variant names:

• chr17-79119947-A-G
• rs2612781
• NM_001350451.2:c.-33-4199T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001350451.2(RBFOX3):​c.-33-4199T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 152,086 control chromosomes in the GnomAD database, including 8,918 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 0.34 (8918 hom., cov: 33)
• Consequence: RBFOX3 NM_001350451.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.421
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX3	NM_001350451.2	c.-33-4199T>C		intron_variant	Intron 4 of 14	ENST00000693108.1	NP_001337380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX3	ENST00000693108.1	c.-33-4199T>C		intron_variant	Intron 4 of 14		NM_001350451.2	ENSP00000510395.1

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51971 AN: 151966 Hom.: 8909 Cov.: 33

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.341

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

GnomAD4 genome AF: 0.342 AC: 52001 AN: 152086 Hom.: 8918 Cov.: 33 AF XY: 0.340 AC XY: 25276 AN XY: 74338

African (AFR) AF: 0.326 AC: 13504 AN: 41462

American (AMR) AF: 0.315 AC: 4811 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1334 AN: 3468

East Asian (EAS) AF: 0.277 AC: 1434 AN: 5184

South Asian (SAS) AF: 0.280 AC: 1350 AN: 4822

European-Finnish (FIN) AF: 0.369 AC: 3903 AN: 10586

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24552 AN: 67972

Other (OTH) AF: 0.337 AC: 714 AN: 2116

Alfa AF: 0.359 Hom.: 15659

Bravo AF: 0.337

Asia WGS AF: 0.268 AC: 933 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.1
DANN	Benign	0.79
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2612781; hg19: chr17-77116029;