chr17-79115654-T-C

Variant names:

• chr17-79115654-T-C
• rs1167103679
• NM_001350451.2:c.62A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001350451.2(RBFOX3):​c.62A>G​(p.Glu21Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000099 in 1,009,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E21K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: RBFOX3 NM_001350451.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3253514).

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.62A>G	p.Glu21Gly	missense	Exon 5 of 15	NP_001337380.1	A0A8I5KWJ3
	RBFOX3	NM_001385804.1		c.62A>G	p.Glu21Gly	missense	Exon 5 of 15	NP_001372733.1
	RBFOX3	NM_001385805.1		c.62A>G	p.Glu21Gly	missense	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.62A>G	p.Glu21Gly	missense	Exon 5 of 15	ENSP00000510395.1	A0A8I5KWJ3
	RBFOX3	ENST00000857749.1		c.62A>G	p.Glu21Gly	missense	Exon 5 of 15	ENSP00000527808.1
	RBFOX3	ENST00000583458.5	TSL:5	c.62A>G	p.Glu21Gly	missense	Exon 4 of 14	ENSP00000464186.1	J3QRF4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.90e-7 AC: 1 AN: 1009856 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 488568

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20780

American (AMR) AF: 0.00 AC: 0 AN: 14810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12288

East Asian (EAS) AF: 0.00 AC: 0 AN: 17306

South Asian (SAS) AF: 0.00 AC: 0 AN: 52240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3880

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 832288

Other (OTH) AF: 0.00 AC: 0 AN: 38728

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.5
PrimateAI	Uncertain	0.75	T
Sift4G	Benign	0.061	T
Polyphen		0.99	D
Vest4		0.45
MutPred		0.19		Loss of stability (P = 0.0385)
MVP		0.45
ClinPred		0.94	D
GERP RS		4.3
PromoterAI		-0.019	Neutral
Varity_R		0.53
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1167103679; hg19: chr17-77111736;