chr17-79115654-T-G

Variant names:

• chr17-79115654-T-G
• rs1167103679
• NM_001350451.2:c.62A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001350451.2(RBFOX3):​c.62A>C​(p.Glu21Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000126 in 1,113,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E21K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RBFOX3 NM_001350451.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46
• 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, NO_KNOWN Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31354433).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

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.62A>C	p.Glu21Ala	missense	Exon 5 of 15	NP_001337380.1	A0A8I5KWJ3
	RBFOX3	NM_001385804.1		c.62A>C	p.Glu21Ala	missense	Exon 5 of 15	NP_001372733.1
	RBFOX3	NM_001385805.1		c.62A>C	p.Glu21Ala	missense	Exon 6 of 16	NP_001372734.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	ENST00000693108.1	MANE Select	c.62A>C	p.Glu21Ala	missense	Exon 5 of 15	ENSP00000510395.1	A0A8I5KWJ3
	RBFOX3	ENST00000857749.1		c.62A>C	p.Glu21Ala	missense	Exon 5 of 15	ENSP00000527808.1
	RBFOX3	ENST00000583458.5	TSL:5	c.62A>C	p.Glu21Ala	missense	Exon 4 of 14	ENSP00000464186.1	J3QRF4

Frequencies

GnomAD3 genomes AF: 0.0000193 AC: 2 AN: 103792 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000373

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 12 AN: 1009862 Hom.: 0 Cov.: 21 AF XY: 0.0000123 AC XY: 6 AN XY: 488568

African (AFR) AF: 0.00 AC: 0 AN: 20780

American (AMR) AF: 0.00 AC: 0 AN: 14810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12288

East Asian (EAS) AF: 0.00 AC: 0 AN: 17306

South Asian (SAS) AF: 0.00 AC: 0 AN: 52240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3880

European-Non Finnish (NFE) AF: 0.0000144 AC: 12 AN: 832294

Other (OTH) AF: 0.00 AC: 0 AN: 38728

GnomAD4 genome AF: 0.0000193 AC: 2 AN: 103792 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 48078

African (AFR) AF: 0.00 AC: 0 AN: 26450

American (AMR) AF: 0.00 AC: 0 AN: 7888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2870

East Asian (EAS) AF: 0.00 AC: 0 AN: 3302

South Asian (SAS) AF: 0.00 AC: 0 AN: 2844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.0000373 AC: 2 AN: 53652

Other (OTH) AF: 0.00 AC: 0 AN: 1434

Alfa AF: 0.0000936 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Idiopathic generalized epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Benign	0.79
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.5
PrimateAI	Uncertain	0.78	T
Sift4G	Benign	0.21	T
Polyphen		0.98	D
Vest4		0.38
MutPred		0.25		Loss of solvent accessibility (P = 0.0224)
MVP		0.41
ClinPred		0.84	D
GERP RS		4.3
PromoterAI		0.031	Neutral
Varity_R		0.55
gMVP		0.30
Mutation Taster		=35/65	disease causing

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: rs1167103679; hg19: chr17-77111736;