NM_018723.4:c.1057G>C

Variant names:

• chr16-7709117-G-C
• rs145873257
• NM_018723.4:c.1057G>C

Variant summary

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

The NM_018723.4(RBFOX1):​c.1057G>C​(p.Gly353Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RBFOX1 NM_018723.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56

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 rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.1057G>C	p.Gly353Arg	missense_variant	Exon 15 of 16	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.1173G>C	p.Thr391Thr	synonymous_variant	Exon 13 of 14	ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.1057G>C	p.Gly353Arg	missense_variant	Exon 15 of 16	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.1173G>C	p.Thr391Thr	synonymous_variant	Exon 13 of 14	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;T;T;.;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.34	.;N;.;N;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.038	D;D;D;D;D;D;D;D
Polyphen		0.99	D;P;D;P;D;P;.;.
Vest4		0.82
MutPred		0.47		.;.;Gain of methylation at G396 (P = 0.0322);.;.;.;.;.;
MVP		0.63
MPC		1.5
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.50
gMVP		0.25

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: rs145873257; hg19: chr16-7759119;