rs376060745

Positions:

• chr17-79115697-G-A
• chr17-79115697-G-C
• chr17-79115697-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001350451.2(RBFOX3):​c.19C>T​(p.Pro7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000084 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBFOX3 NM_001350451.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.94

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02852559).
• BP6: Variant 17-79115697-G-A is Benign according to our data. Variant chr17-79115697-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460021.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX3	NM_001350451.2	c.19C>T	p.Pro7Ser	missense_variant	5/15	ENST00000693108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX3	ENST00000693108.1	c.19C>T	p.Pro7Ser	missense_variant	5/15		NM_001350451.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 52 AN: 151710 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000117 AC: 10 AN: 85296 Hom.: 0 AF XY: 0.0000656 AC XY: 3 AN XY: 45720

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.0000567

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000283

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000385

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000836 AC: 53 AN: 634050 Hom.: 5 Cov.: 9 AF XY: 0.0000932 AC XY: 31 AN XY: 332634

Gnomad4 AFR exome AF: 0.000713

Gnomad4 AMR exome AF: 0.0000377

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000354

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000462

Gnomad4 OTH exome AF: 0.000972

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000342 AC: 52 AN: 151826 Hom.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 26 AN XY: 74196

Gnomad4 AFR AF: 0.000967

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000336

ExAC AF: 0.000142 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Idiopathic generalized epilepsy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.029	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0050	.;.;B;.
Vest4		0.11
MutPred		0.11		Gain of phosphorylation at P7 (P = 0.0405);Gain of phosphorylation at P7 (P = 0.0405);Gain of phosphorylation at P7 (P = 0.0405);Gain of phosphorylation at P7 (P = 0.0405);
MVP		0.18
ClinPred		0.030	T
GERP RS		4.3
Varity_R		0.075
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs376060745; hg19: chr17-77111779;