17-79212099-C-T

Variant names:

• chr17-79212099-C-T
• rs16972153
• NM_001350451.2:c.-34+23667G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001350451.2(RBFOX3):​c.-34+23667G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0434 in 152,332 control chromosomes in the GnomAD database, including 172 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 0.043 (172 hom., cov: 33)
• Consequence: RBFOX3 NM_001350451.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.205
• 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=-0.8).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0434 (6616/152332) while in subpopulation NFE AF = 0.049 (3335/68022). AF 95% confidence interval is 0.0476. There are 172 homozygotes in GnomAd4. There are 3115 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6616 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX3	NM_001350451.2	c.-34+23667G>A		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.-34+23667G>A		intron_variant	Intron 4 of 14		NM_001350451.2	ENSP00000510395.1

Frequencies

GnomAD3 genomes AF: 0.0435 AC: 6619 AN: 152214 Hom.: 172 Cov.: 33

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0614

Gnomad EAS AF: 0.0261

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0490

Gnomad OTH AF: 0.0435

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

GnomAD4 genome AF: 0.0434 AC: 6616 AN: 152332 Hom.: 172 Cov.: 33 AF XY: 0.0418 AC XY: 3115 AN XY: 74488

African (AFR) AF: 0.0441 AC: 1832 AN: 41572

American (AMR) AF: 0.0331 AC: 507 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0614 AC: 213 AN: 3468

East Asian (EAS) AF: 0.0260 AC: 135 AN: 5192

South Asian (SAS) AF: 0.0267 AC: 129 AN: 4828

European-Finnish (FIN) AF: 0.0332 AC: 353 AN: 10620

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0490 AC: 3335 AN: 68022

Other (OTH) AF: 0.0430 AC: 91 AN: 2116

Alfa AF: 0.0402 Hom.: 69

Bravo AF: 0.0419

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.67
PhyloP100		0.20
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: rs16972153; hg19: chr17-77208181;