16-7518256-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000550418.6(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 ENST00000550418.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• autism susceptibility 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000550418.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	NM_018723.4	MANE Select	c.137C>T	p.Pro46Leu	missense	Exon 5 of 16	NP_061193.2
	RBFOX1	NM_145893.3	MANE Plus Clinical	c.197C>T	p.Pro66Leu	missense	Exon 2 of 14	NP_665900.1
	RBFOX1	NM_001415887.1		c.734C>T	p.Pro245Leu	missense	Exon 8 of 20	NP_001402816.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	ENST00000550418.6	TSL:1 MANE Select	c.137C>T	p.Pro46Leu	missense	Exon 5 of 16	ENSP00000450031.1
	RBFOX1	ENST00000355637.9	TSL:1 MANE Plus Clinical	c.197C>T	p.Pro66Leu	missense	Exon 2 of 14	ENSP00000347855.4
	RBFOX1	ENST00000311745.9	TSL:1	c.197C>T	p.Pro66Leu	missense	Exon 2 of 13	ENSP00000309117.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Idiopathic generalized epilepsy (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.086	T
Polyphen		0.49	P
Vest4		0.68
MutPred		0.38		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

Other links and lift over

dbSNP: rs113298071; hg19: chr16-7568258;