rs547643968

Variant names:

• chr17-79097428-C-A
• rs547643968
• NM_001350451.2:c.623-4G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001350451.2(RBFOX3):​c.623-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,542,928 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (7 hom.)
• Consequence: RBFOX3 NM_001350451.2 splice_region, intron
• Scores: Splicing: ADA: 0.0003240
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.30
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-79097428-C-A is Benign according to our data. Variant chr17-79097428-C-A is described in ClinVar as Benign. ClinVar VariationId is 529524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 239 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.623-4G>T		splice_region intron	N/A	NP_001337380.1	A0A8I5KWJ3
	RBFOX3	NM_001385804.1		c.623-4G>T		splice_region intron	N/A	NP_001372733.1
	RBFOX3	NM_001385805.1		c.623-4G>T		splice_region intron	N/A	NP_001372734.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	ENST00000693108.1	MANE Select	c.623-4G>T		splice_region intron	N/A	ENSP00000510395.1	A0A8I5KWJ3
	RBFOX3	ENST00000857749.1		c.719-4G>T		splice_region intron	N/A	ENSP00000527808.1
	RBFOX3	ENST00000583458.5	TSL:5	c.620-4G>T		splice_region intron	N/A	ENSP00000464186.1	J3QRF4

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152022 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00934

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00151 AC: 212 AN: 140772 AF XY: 0.00139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000333

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00798

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.00106 AC: 1477 AN: 1390790 Hom.: 7 Cov.: 34 AF XY: 0.00107 AC XY: 730 AN XY: 685000

African (AFR) AF: 0.0000318 AC: 1 AN: 31422

American (AMR) AF: 0.000398 AC: 14 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 63 AN: 24856

East Asian (EAS) AF: 0.00 AC: 0 AN: 35594

South Asian (SAS) AF: 0.00 AC: 0 AN: 78668

European-Finnish (FIN) AF: 0.00828 AC: 394 AN: 47584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4882

European-Non Finnish (NFE) AF: 0.000879 AC: 945 AN: 1075022

Other (OTH) AF: 0.00104 AC: 60 AN: 57578

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152138 Hom.: 0 Cov.: 31 AF XY: 0.00176 AC XY: 131 AN XY: 74360

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00934 AC: 99 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 67958

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.000578

ClinVar

ClinVar submissions

Significance: 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	-0.67
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		-1.3
PromoterAI		-0.039	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.12		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: rs547643968; hg19: chr17-77093510;