17-79094499-C-T

Variant names:

• chr17-79094499-C-T
• rs373093807
• NM_001350451.2:c.1029G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001350451.2(RBFOX3):​c.1029G>A​(p.Pro343Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000735 in 1,224,350 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: RBFOX3 NM_001350451.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.26
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 17-79094499-C-T is Benign according to our data. Variant chr17-79094499-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 460025.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.26 with no splicing effect.
• BS2: High AC in GnomAd4 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.1029G>A	p.Pro343Pro	synonymous	Exon 14 of 15	NP_001337380.1	A0A8I5KWJ3
	RBFOX3	NM_001385804.1		c.1029G>A	p.Pro343Pro	synonymous	Exon 14 of 15	NP_001372733.1
	RBFOX3	NM_001385805.1		c.1029G>A	p.Pro343Pro	synonymous	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.1029G>A	p.Pro343Pro	synonymous	Exon 14 of 15	ENSP00000510395.1	A0A8I5KWJ3
	RBFOX3	ENST00000857749.1		c.1125G>A	p.Pro375Pro	synonymous	Exon 14 of 15	ENSP00000527808.1
	RBFOX3	ENST00000583458.5	TSL:5	c.1026G>A	p.Pro342Pro	synonymous	Exon 13 of 14	ENSP00000464186.1	J3QRF4

Frequencies

GnomAD3 genomes AF: 0.0000886 AC: 12 AN: 135392 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000514

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000622

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000588 AC: 5 AN: 85054 AF XY: 0.0000215

Gnomad AFR exome AF: 0.000354

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000282

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000716 AC: 78 AN: 1088856 Hom.: 0 Cov.: 31 AF XY: 0.0000661 AC XY: 35 AN XY: 529526

African (AFR) AF: 0.000362 AC: 7 AN: 19314

American (AMR) AF: 0.00 AC: 0 AN: 14352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14328

East Asian (EAS) AF: 0.000134 AC: 1 AN: 7456

South Asian (SAS) AF: 0.0000299 AC: 2 AN: 66864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3970

European-Non Finnish (NFE) AF: 0.0000735 AC: 66 AN: 897628

Other (OTH) AF: 0.0000508 AC: 2 AN: 39378

GnomAD4 genome AF: 0.0000886 AC: 12 AN: 135494 Hom.: 0 Cov.: 29 AF XY: 0.000123 AC XY: 8 AN XY: 64814

African (AFR) AF: 0.000163 AC: 6 AN: 36764

American (AMR) AF: 0.00 AC: 0 AN: 12626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3320

East Asian (EAS) AF: 0.000514 AC: 2 AN: 3894

South Asian (SAS) AF: 0.00 AC: 0 AN: 3920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.0000622 AC: 4 AN: 64302

Other (OTH) AF: 0.00 AC: 0 AN: 1910

Alfa AF: 0.0000582 Hom.: 0

Bravo AF: 0.0000642

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373093807; hg19: chr17-77090581; COSMIC: COSV104434502;