chr16-7333056-C-T

Position:

• chr16-7333056-C-T

Variant summary

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

The NM_145893.3(RBFOX1):​c.55C>T​(p.Pro19Ser) variant causes a missense change. 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. P19L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBFOX1 NM_145893.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28

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_145893.3	c.55C>T	p.Pro19Ser	missense_variant	1/14	ENST00000355637.9
RBFOX1	NM_018723.4	c.28-185091C>T		intron_variant		ENST00000550418.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX1	ENST00000355637.9	c.55C>T	p.Pro19Ser	missense_variant	1/14	1	NM_145893.3
RBFOX1	ENST00000550418.6	c.28-185091C>T		intron_variant		1	NM_018723.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250590 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135436

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

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

Dec 01, 2023

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 19 of the RBFOX1 protein (p.Pro19Ser). This variant is present in population databases (rs773668882, gnomAD 0.003%). 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: 842364). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N;N;N;N;.
REVEL	Benign	0.24
Sift	Uncertain	0.017	D;D;D;D;.
Sift4G	Benign	0.074	T;T;T;T;T
Polyphen		1.0	D;D;D;.;.
Vest4		0.70
MutPred		0.47		.;.;.;Loss of disorder (P = 0.0809);Loss of disorder (P = 0.0809);
MVP		0.22
MPC		0.017
ClinPred		0.80	D
GERP RS		5.8

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: rs773668882; hg19: chr16-7383057; COSMIC: COSV100301679; COSMIC: COSV100301679;