16-7518352-C-G

Position:

• chr16-7518352-C-G

Variant summary

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

The NM_018723.4(RBFOX1):​c.233C>G​(p.Ala78Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBFOX1 NM_018723.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.05

Genes affected

RBFOX1 (HGNC:18222): (RNA binding fox-1 homolog 1) The Fox-1 family of RNA-binding proteins is evolutionarily conserved, and regulates tissue-specific alternative splicing in metazoa. Fox-1 recognizes a (U)GCAUG stretch in regulated exons or in flanking introns. The protein binds to the C-terminus of ataxin-2 and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the product of the SCA2 gene which causes familial neurodegenerative diseases. Fox-1 and ataxin-2 are both localized in the trans-Golgi network. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

RBFOX1 (HGNC:):

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=0.14658454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.233C>G	p.Ala78Gly	missense_variant	5/16	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.293C>G	p.Ala98Gly	missense_variant	2/14	ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.233C>G	p.Ala78Gly	missense_variant	5/16	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.293C>G	p.Ala98Gly	missense_variant	2/14	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 30, 2022

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 98 of the RBFOX1 protein (p.Ala98Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RBFOX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 529518). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	.;.;.;T;.;T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L;L;.;.;.;.;.;L;.;.;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;.
REVEL	Benign	0.017
Sift	Benign	0.14	.;T;D;D;D;D;T;D;D;D;D;D;D;D;.;.
Sift4G	Benign	0.24	.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.017, 0.038, 0.77, 0.0040, 0.51, 0.0010, 0.24, 0.81	.;.;B;B;P;B;P;.;.;B;B;B;P;.;.;.
Vest4		0.36, 0.42, 0.36, 0.33, 0.55, 0.36, 0.41, 0.35, 0.34, 0.37, 0.32, 0.53
MutPred		0.32		.;.;.;.;Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);.;.;.;.;.;.;.;.;.;.;
MVP		0.21
MPC		0.0060
ClinPred		0.49	T
GERP RS		4.3
Varity_R		0.19
gMVP		0.45

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: rs761205127; hg19: chr16-7568354;