17-79094484-G-C

Variant names:

• chr17-79094484-G-C
• rs1258215929
• NM_001350451.2:c.1044C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001350451.2(RBFOX3):​c.1044C>G​(p.Ile348Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000227 in 1,319,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I348I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: RBFOX3 NM_001350451.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.797
• Publications: 1 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, NO_KNOWN Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23623636).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	NM_001350451.2	MANE Select	c.1044C>G	p.Ile348Met	missense	Exon 14 of 15	NP_001337380.1	A0A8I5KWJ3
	RBFOX3	NM_001385804.1		c.1044C>G	p.Ile348Met	missense	Exon 14 of 15	NP_001372733.1
	RBFOX3	NM_001385805.1		c.1044C>G	p.Ile348Met	missense	Exon 15 of 16	NP_001372734.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	ENST00000693108.1	MANE Select	c.1044C>G	p.Ile348Met	missense	Exon 14 of 15	ENSP00000510395.1	A0A8I5KWJ3
	RBFOX3	ENST00000857749.1		c.1140C>G	p.Ile380Met	missense	Exon 14 of 15	ENSP00000527808.1
	RBFOX3	ENST00000583458.5	TSL:5	c.1041C>G	p.Ile347Met	missense	Exon 13 of 14	ENSP00000464186.1	J3QRF4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000227 AC: 3 AN: 1319516 Hom.: 0 Cov.: 31 AF XY: 0.00000463 AC XY: 3 AN XY: 647560

African (AFR) AF: 0.00 AC: 0 AN: 26294

American (AMR) AF: 0.00 AC: 0 AN: 22406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22712

East Asian (EAS) AF: 0.00 AC: 0 AN: 28928

South Asian (SAS) AF: 0.00 AC: 0 AN: 70324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.00000287 AC: 3 AN: 1043680

Other (OTH) AF: 0.00 AC: 0 AN: 54580

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.64
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.80
PrimateAI	Benign	0.38	T
Sift4G	Uncertain	0.035	D
Polyphen		0.99	D
Vest4		0.60
MutPred		0.48		Gain of disorder (P = 0.0318)
MVP		0.11
ClinPred		0.91	D
GERP RS		-1.8
Varity_R		0.25
gMVP		0.43
Mutation Taster		=61/39	polymorphism

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: rs1258215929; hg19: chr17-77090566;