rs547643968

chr17-79097428-C-A

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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. 2/2 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003240
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.30

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 529524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 239 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX3	NM_001350451.2	c.623-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000693108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX3	ENST00000693108.1	c.623-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001350451.2

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

GnomAD3 exomes AF: 0.00151 AC: 212 AN: 140772 Hom.: 0 AF XY: 0.00139 AC XY: 106 AN XY: 76330

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 SAS 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

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.000398

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00828

Gnomad4 NFE exome AF: 0.000879

Gnomad4 OTH exome AF: 0.00104

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00934

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.000578

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	13
Dann	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs547643968; hg19: chr17-77093510;