17-79115697-G-T

Position:

• chr17-79115697-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001350451.2(RBFOX3):​c.19C>A​(p.Pro7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBFOX3 NM_001350451.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07646063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX3	NM_001350451.2	c.19C>A	p.Pro7Thr	missense_variant	5/15	ENST00000693108.1	NP_001337380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBFOX3	ENST00000693108.1	c.19C>A	p.Pro7Thr	missense_variant	5/15		NM_001350451.2	ENSP00000510395.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000158 AC: 1 AN: 634048 Hom.: 0 Cov.: 9 AF XY: 0.00000301 AC XY: 1 AN XY: 332634

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000475 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.0099	.;.;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;T;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.076	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;L;L
PrimateAI	Uncertain	0.64	T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.092
MutPred		0.16		Gain of phosphorylation at P7 (P = 0.0097);Gain of phosphorylation at P7 (P = 0.0097);Gain of phosphorylation at P7 (P = 0.0097);Gain of phosphorylation at P7 (P = 0.0097);
MVP		0.18
ClinPred		0.37	T
GERP RS		4.3
Varity_R		0.10
gMVP		0.30

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;