chr17-79115653-C-T

Variant names:

• chr17-79115653-C-T
• rs565537117
• NM_001350451.2:c.63G>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.63G>A​(p.Glu21Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,322,094 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: RBFOX3 NM_001350451.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.687
• 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=-0.4).
• BP6: Variant 17-79115653-C-T is Benign according to our data. Variant chr17-79115653-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 416626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.687 with no splicing effect.
• BS2: High AC in GnomAd4 at 181 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.63G>A	p.Glu21Glu	synonymous	Exon 5 of 15	NP_001337380.1	A0A8I5KWJ3
	RBFOX3	NM_001385804.1		c.63G>A	p.Glu21Glu	synonymous	Exon 5 of 15	NP_001372733.1
	RBFOX3	NM_001385805.1		c.63G>A	p.Glu21Glu	synonymous	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.63G>A	p.Glu21Glu	synonymous	Exon 5 of 15	ENSP00000510395.1	A0A8I5KWJ3
	RBFOX3	ENST00000857749.1		c.63G>A	p.Glu21Glu	synonymous	Exon 5 of 15	ENSP00000527808.1
	RBFOX3	ENST00000583458.5	TSL:5	c.63G>A	p.Glu21Glu	synonymous	Exon 4 of 14	ENSP00000464186.1	J3QRF4

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 181 AN: 133936 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00368

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00324

GnomAD2 exomes AF: 0.00141 AC: 73 AN: 51770 AF XY: 0.00173

Gnomad AFR exome AF: 0.000457

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00122

GnomAD4 exome AF: 0.00200 AC: 2382 AN: 1188086 Hom.: 6 Cov.: 21 AF XY: 0.00213 AC XY: 1233 AN XY: 579298

African (AFR) AF: 0.000478 AC: 12 AN: 25124

American (AMR) AF: 0.000548 AC: 11 AN: 20072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17490

East Asian (EAS) AF: 0.00 AC: 0 AN: 28256

South Asian (SAS) AF: 0.00400 AC: 236 AN: 58986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27872

Middle Eastern (MID) AF: 0.000819 AC: 4 AN: 4884

European-Non Finnish (NFE) AF: 0.00211 AC: 2014 AN: 956512

Other (OTH) AF: 0.00215 AC: 105 AN: 48890

GnomAD4 genome AF: 0.00135 AC: 181 AN: 134008 Hom.: 0 Cov.: 26 AF XY: 0.00142 AC XY: 91 AN XY: 64162

African (AFR) AF: 0.000603 AC: 21 AN: 34842

American (AMR) AF: 0.00229 AC: 28 AN: 12202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3336

East Asian (EAS) AF: 0.00 AC: 0 AN: 4482

South Asian (SAS) AF: 0.00418 AC: 17 AN: 4070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7798

Middle Eastern (MID) AF: 0.00397 AC: 1 AN: 252

European-Non Finnish (NFE) AF: 0.00168 AC: 108 AN: 64300

Other (OTH) AF: 0.00321 AC: 6 AN: 1872

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00124

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	-0.40
CADD	Benign	9.6
DANN	Benign	0.52
PhyloP100		0.69
PromoterAI		0.0051	Neutral
Mutation Taster		=97/3	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: rs565537117; hg19: chr17-77111735; COSMIC: COSV107518842; COSMIC: COSV107518842;