16-7518256-C-T

Position:

• chr16-7518256-C-T

Variant summary

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

The NM_018723.4(RBFOX1):​c.137C>T​(p.Pro46Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P46H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBFOX1 NM_018723.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX1	NM_018723.4	c.137C>T	p.Pro46Leu	missense_variant	5/16	ENST00000550418.6
RBFOX1	NM_145893.3	c.197C>T	p.Pro66Leu	missense_variant	2/14	ENST00000355637.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX1	ENST00000550418.6	c.137C>T	p.Pro46Leu	missense_variant	5/16	1	NM_018723.4	A1
RBFOX1	ENST00000355637.9	c.197C>T	p.Pro66Leu	missense_variant	2/14	1	NM_145893.3

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

Invitae

Jan 15, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RBFOX1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 66 of the RBFOX1 protein (p.Pro66Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;.;.;T;.;T;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.2	.;.;M;M;.;.;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.1	.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
Sift4G	Benign	0.086	.;T;T;T;D;D;T;D;T;T;D;D;D;D;D;T
Polyphen		0.49, 1.0, 0.98, 0.97, 1.0, 1.0	.;.;P;D;D;D;D;.;.;D;D;D;D;.;.;.
Vest4		0.68, 0.79, 0.75, 0.69, 0.64, 0.73, 0.78, 0.68, 0.68, 0.73, 0.65, 0.73
MutPred		0.38		.;.;.;.;Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;.;.;.;.;.;.;.;.;.;
MVP		0.15
MPC		0.017
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.45
gMVP		0.49

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: rs113298071; hg19: chr16-7568258;