9-132264514-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015046.7(SETX):c.7759A>G(p.Ile2587Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,704 control chromosomes in the GnomAD database, including 103,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 18120 hom., cov: 31)

Exomes 𝑓: 0.32 ( 85599 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -1.19

Variant links:

Genes affected

SETX (HGNC:445): (senataxin) This gene encodes a protein named for its homology to the Sen1p protein of fungi which has RNA helicase activity encoded by a domain at the C-terminal end of the protein. The protein encoded by this gene contains a DNA/RNA helicase domain at its C-terminal end which suggests that it may be involved in both DNA and RNA processing. Mutations in this gene have been associated with ataxia-ocular apraxia-2 (AOA2) and an autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS4). [provided by RefSeq, Jul 2008]

SETX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2665112E-6).

BP6

Variant 9-132264514-T-C is Benign according to our data. Variant chr9-132264514-T-C is described in ClinVar as [Benign]. Clinvar id is 95669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132264514-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.7759A>G	p.Ile2587Val	missense_variant	Exon 26 of 26	ENST00000224140.6	NP_055861.3	Q7Z333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SETX	ENST00000224140.6 link	c.7759A>G	p.Ile2587Val	missense_variant	Exon 26 of 26	1	NM_015046.7	ENSP00000224140.5	Q7Z333-1
SETX	ENST00000436441.5 link	c.2572A>G	p.Ile858Val	missense_variant	Exon 17 of 17	5		ENSP00000409143.1	X6RI79
SETX	ENST00000477049.1 link	n.909A>G		non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.444

AC:

67461

AN:

151896

Hom.:

18073

Cov.:

show subpopulations

Gnomad AFR

AF:

0.746

Gnomad AMI

AF:

0.200

Gnomad AMR

AF:

0.357

Gnomad ASJ

AF:

0.396

Gnomad EAS

AF:

0.714

Gnomad SAS

AF:

0.453

Gnomad FIN

AF:

0.293

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.289

Gnomad OTH

AF:

0.418

GnomAD3 exomes

AF:

0.383

AC:

96108

AN:

251178

Hom.:

21414

AF XY:

0.378

AC XY:

51299

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.756

Gnomad AMR exome

AF:

0.316

Gnomad ASJ exome

AF:

0.388

Gnomad EAS exome

AF:

0.727

Gnomad SAS exome

AF:

0.441

Gnomad FIN exome

AF:

0.297

Gnomad NFE exome

AF:

0.295

Gnomad OTH exome

AF:

0.356

GnomAD4 exome

AF:

0.323

AC:

471972

AN:

1461690

Hom.:

85599

Cov.:

AF XY:

0.326

AC XY:

237034

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.763

Gnomad4 AMR exome

AF:

0.321

Gnomad4 ASJ exome

AF:

0.385

Gnomad4 EAS exome

AF:

0.737

Gnomad4 SAS exome

AF:

0.438

Gnomad4 FIN exome

AF:

0.300

Gnomad4 NFE exome

AF:

0.282

Gnomad4 OTH exome

AF:

0.372

GnomAD4 genome

AF:

0.444

AC:

67565

AN:

152014

Hom.:

18120

Cov.:

AF XY:

0.444

AC XY:

32992

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.746

Gnomad4 AMR

AF:

0.358

Gnomad4 ASJ

AF:

0.396

Gnomad4 EAS

AF:

0.714

Gnomad4 SAS

AF:

0.453

Gnomad4 FIN

AF:

0.293

Gnomad4 NFE

AF:

0.289

Gnomad4 OTH

AF:

0.416

Alfa

AF:

0.331

Hom.:

24228

Bravo

AF:

0.465

TwinsUK

AF:

0.274

AC:

1017

ALSPAC

AF:

0.284

AC:

1095

ESP6500AA

AF:

0.732

AC:

3227

ESP6500EA

AF:

0.297

AC:

2550

ExAC

AF:

0.392

AC:

47626

Asia WGS

AF:

0.576

AC:

2005

AN:

3478

EpiCase

AF:

0.304

EpiControl

AF:

0.307

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:11

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Apr 29, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 14, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 4

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Nov 17, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.0060

DANN

Benign

0.20

DEOGEN2

Benign

0.088

.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.12

T;T

MetaRNN

Benign

0.0000013

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.55

.;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.22

N;N

REVEL

Benign

0.19

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.0040

MPC

0.063

ClinPred

0.0010

GERP RS

-3.8

Varity_R

0.014

gMVP

0.072

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