NM_001350451.2:c.-175+67677A>G

Variant names:

• chr17-79414777-T-C
• rs1316453
• NM_001350451.2:c.-175+67677A>G

Variant summary

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

The NM_001350451.2(RBFOX3):​c.-175+67677A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 150,130 control chromosomes in the GnomAD database, including 7,240 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 0.29 (7240 hom., cov: 33)
• Consequence: RBFOX3 NM_001350451.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX3	NM_001350451.2	c.-175+67677A>G		intron_variant	Intron 2 of 14	ENST00000693108.1	NP_001337380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX3	ENST00000693108.1	c.-175+67677A>G		intron_variant	Intron 2 of 14		NM_001350451.2	ENSP00000510395.1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 42825 AN: 150018 Hom.: 7239 Cov.: 33

Gnomad AFR AF: 0.0877

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.285 AC: 42822 AN: 150130 Hom.: 7240 Cov.: 33 AF XY: 0.288 AC XY: 21163 AN XY: 73454

African (AFR) AF: 0.0876 AC: 3464 AN: 39556

American (AMR) AF: 0.324 AC: 4934 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1503 AN: 3468

East Asian (EAS) AF: 0.417 AC: 2155 AN: 5168

South Asian (SAS) AF: 0.304 AC: 1468 AN: 4832

European-Finnish (FIN) AF: 0.376 AC: 3981 AN: 10590

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24348 AN: 67972

Other (OTH) AF: 0.308 AC: 646 AN: 2098

Alfa AF: 0.312 Hom.: 8322

Bravo AF: 0.267

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.4
DANN	Benign	0.31
PhyloP100		-1.3
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: rs1316453; hg19: chr17-77410859; COSMIC: COSV70562977;