16-7518256-C-A

Position:

chr16-7518256-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000550418.6(RBFOX1):c.137C>A(p.Pro46His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,614,146 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P46L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0031 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 5 hom. )

Consequence

RBFOX1
ENST00000550418.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.31

Variant links:

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 links:

RBFOX1 (HGNC:):

RBFOX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00788638).

BP6

Variant 16-7518256-C-A is Benign according to our data. Variant chr16-7518256-C-A is described in ClinVar as [Benign]. Clinvar id is 415956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-7518256-C-A is described in Lovd as [Likely_benign]. Variant chr16-7518256-C-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 478 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX1	NM_018723.4 linkuse as main transcript	c.137C>A	p.Pro46His	missense_variant	5/16	ENST00000550418.6	NP_061193.2	Q9NWB1-1Q59HD3
RBFOX1	NM_145893.3 linkuse as main transcript	c.197C>A	p.Pro66His	missense_variant	2/14	ENST00000355637.9	NP_665900.1	Q9NWB1-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6 linkuse as main transcript	c.137C>A	p.Pro46His	missense_variant	5/16	1	NM_018723.4	ENSP00000450031.1		Q9NWB1-1
RBFOX1	ENST00000355637.9 linkuse as main transcript	c.197C>A	p.Pro66His	missense_variant	2/14	1	NM_145893.3	ENSP00000347855.4		Q9NWB1-5

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

476

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000816

AC:

205

AN:

251348

Hom.:

AF XY:

0.000560

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.0112

Gnomad AMR exome

AF:

0.000608

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:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000300

AC:

438

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

177

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0111

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.00314

AC:

478

AN:

152288

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

229

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0109

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000747

Hom.:

Bravo

AF:

0.00332

ESP6500AA

AF:

0.0121

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00101

AC:

122

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Idiopathic generalized epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

.;.;.;T;.;T;.;.;.;T;.;.;.;.;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D;D;.;D;D;T;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0079

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.2

.;.;M;M;.;.;.;.;.;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.1

.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.025

.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.

Sift4G

Uncertain

0.018

.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.0070, 1.0, 1.0

.;.;B;D;D;D;D;.;.;D;D;D;D;.;.;.

Vest4

0.67, 0.77, 0.74, 0.71, 0.64, 0.75, 0.73, 0.72, 0.77, 0.68, 0.68

MVP

0.13

MPC

0.016

ClinPred

0.032

GERP RS

4.8

Varity_R

0.43

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over