chr16-7518256-C-G

Variant names:

• chr16-7518256-C-G
• rs113298071
• NM_018723.4:c.137C>G

Variant summary

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

The NM_018723.4(RBFOX1):​c.137C>G​(p.Pro46Arg) variant causes a missense change involving the alteration of a 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P46H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBFOX1 NM_018723.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.137C>G	p.Pro46Arg	missense_variant	Exon 5 of 16	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.197C>G	p.Pro66Arg	missense_variant	Exon 2 of 14	ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.137C>G	p.Pro46Arg	missense_variant	Exon 5 of 16	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.197C>G	p.Pro66Arg	missense_variant	Exon 2 of 14	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;.;.;T;.;T;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.52	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;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0030	.;D;D;D;D;D;D;D;D;D;T;T;T;D;.;.
Sift4G	Benign	0.076	.;T;D;D;D;D;D;D;T;D;D;D;D;D;D;D
Polyphen		0.70, 1.0, 1.0, 1.0	.;.;P;D;D;D;D;.;.;D;D;D;D;.;.;.
Vest4		0.70, 0.83, 0.79, 0.75, 0.69, 0.79, 0.83, 0.73, 0.82, 0.68, 0.74
MutPred		0.31		.;.;.;.;Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;.;.;.;.;.;.;.;.;.;
MVP		0.13
MPC		0.017
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.61
gMVP		0.52

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;