NM_001350451.2:c.166G>T

Variant names:

• chr17-79115550-C-A
• rs748110754
• NM_001350451.2:c.166G>T

Variant summary

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

The NM_001350451.2(RBFOX3):​c.166G>T​(p.Glu56*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000845 in 1,183,230 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. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: RBFOX3 NM_001350451.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.16
• Publications: 0 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	NM_001350451.2	MANE Select	c.166G>T	p.Glu56*	stop_gained	Exon 5 of 15	NP_001337380.1
	RBFOX3	NM_001385804.1		c.166G>T	p.Glu56*	stop_gained	Exon 5 of 15	NP_001372733.1
	RBFOX3	NM_001385805.1		c.166G>T	p.Glu56*	stop_gained	Exon 6 of 16	NP_001372734.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	ENST00000693108.1	MANE Select	c.166G>T	p.Glu56*	stop_gained	Exon 5 of 15	ENSP00000510395.1
	RBFOX3	ENST00000583458.5	TSL:5	c.166G>T	p.Glu56*	stop_gained	Exon 4 of 14	ENSP00000464186.1
	RBFOX3	ENST00000582043.5	TSL:5	c.166G>T	p.Glu56*	stop_gained	Exon 2 of 11	ENSP00000463964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.45e-7 AC: 1 AN: 1183230 Hom.: 0 Cov.: 32 AF XY: 0.00000176 AC XY: 1 AN XY: 568122

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

African (AFR) AF: 0.00 AC: 0 AN: 24020

American (AMR) AF: 0.00 AC: 0 AN: 11944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16344

East Asian (EAS) AF: 0.00 AC: 0 AN: 27416

South Asian (SAS) AF: 0.00 AC: 0 AN: 41484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4896

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 972204

Other (OTH) AF: 0.00 AC: 0 AN: 48264

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		4.2
Vest4		0.46
GERP RS		3.8
PromoterAI		-0.043	Neutral

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: rs748110754; hg19: chr17-77111632;