rs375309858

Positions:

• chr17-79115613-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001350451.2(RBFOX3):​c.103G>A​(p.Gly35Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00043 in 1,285,514 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: RBFOX3 NM_001350451.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.13

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076612234).
• BP6: Variant 17-79115613-C-T is Benign according to our data. Variant chr17-79115613-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460020.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX3	NM_001350451.2	c.103G>A	p.Gly35Ser	missense_variant	5/15	ENST00000693108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX3	ENST00000693108.1	c.103G>A	p.Gly35Ser	missense_variant	5/15		NM_001350451.2

Frequencies

GnomAD3 genomes AF: 0.000521 AC: 67 AN: 128512 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000118

Gnomad AMI AF: 0.0390

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000328

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000297 AC: 18 AN: 60614 Hom.: 0 AF XY: 0.000393 AC XY: 12 AN XY: 30562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000360

Gnomad ASJ exome AF: 0.000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.000576

GnomAD4 exome AF: 0.000420 AC: 486 AN: 1157002 Hom.: 0 Cov.: 31 AF XY: 0.000432 AC XY: 242 AN XY: 560240

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000399

Gnomad4 ASJ exome AF: 0.00327

Gnomad4 EAS exome AF: 0.0000969

Gnomad4 SAS exome AF: 0.0000165

Gnomad4 FIN exome AF: 0.000154

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.000267

GnomAD4 genome AF: 0.000521 AC: 67 AN: 128512 Hom.: 0 Cov.: 31 AF XY: 0.000595 AC XY: 36 AN XY: 60484

Gnomad4 AFR AF: 0.000118

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00181

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000328

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000567

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.0000997 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.103G>A (p.G35S) alteration is located in exon 4 (coding exon 1) of the RBFOX3 gene. This alteration results from a G to A substitution at nucleotide position 103, causing the glycine (G) at amino acid position 35 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Idiopathic generalized epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	.;.;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.0077	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
Sift4G	Benign	0.094	T;T;T;T
Polyphen		1.0	.;.;D;.
Vest4		0.42
MVP		0.35
ClinPred		0.37	T
GERP RS		3.0
Varity_R		0.28
gMVP		0.29

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: rs375309858; hg19: chr17-77111695; COSMIC: COSV99066505; COSMIC: COSV99066505;