9-132298298-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015046.7(SETX):c.5563A>G(p.Thr1855Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,270 control chromosomes in the GnomAD database, including 51,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 11057 hom., cov: 33)

Exomes 𝑓: 0.20 ( 40693 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.716

Publications

45 publications found

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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 4
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
distal hereditary motor neuropathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

SETX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5498156E-6).

BP6

Variant 9-132298298-T-C is Benign according to our data. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in CliVar as Benign. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.5563A>G	p.Thr1855Ala	missense_variant	Exon 13 of 26	ENST00000224140.6	NP_055861.3	Q7Z333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6 link	c.5563A>G	p.Thr1855Ala	missense_variant	Exon 13 of 26	1	NM_015046.7	ENSP00000224140.5		Q7Z333-1
SETX	ENST00000436441.5 link	c.289A>G	p.Thr97Ala	missense_variant	Exon 3 of 17	5		ENSP00000409143.1		X6RI79

Frequencies

GnomAD3 genomes

AF:

0.317

AC:

48237

AN:

152030

Hom.:

11015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.615

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.214

Gnomad ASJ

AF:

0.266

Gnomad EAS

AF:

0.677

Gnomad SAS

AF:

0.381

Gnomad FIN

AF:

0.169

Gnomad MID

AF:

0.325

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.275

GnomAD2 exomes

AF:

0.266

AC:

66814

AN:

251216

AF XY:

0.261

show subpopulations

Gnomad AFR exome

AF:

0.626

Gnomad AMR exome

AF:

0.206

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.695

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.199

AC:

290334

AN:

1460122

Hom.:

40693

Cov.:

AF XY:

0.203

AC XY:

147124

AN XY:

726470

show subpopulations

African (AFR)

AF:

0.632

AC:

21118

AN:

33406

American (AMR)

AF:

0.207

AC:

9240

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

6610

AN:

26118

East Asian (EAS)

AF:

0.713

AC:

28268

AN:

39672

South Asian (SAS)

AF:

0.362

AC:

31182

AN:

86186

European-Finnish (FIN)

AF:

0.169

AC:

9013

AN:

53406

Middle Eastern (MID)

AF:

0.342

AC:

1971

AN:

5768

European-Non Finnish (NFE)

AF:

0.151

AC:

168146

AN:

1110526

Other (OTH)

AF:

0.245

AC:

14786

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

10626

21251

31877

42502

53128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6596

13192

19788

26384

32980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.318

AC:

48333

AN:

152148

Hom.:

11057

Cov.:

AF XY:

0.320

AC XY:

23801

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.616

AC:

25539

AN:

41476

American (AMR)

AF:

0.215

AC:

3284

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.266

AC:

922

AN:

3472

East Asian (EAS)

AF:

0.676

AC:

3499

AN:

5176

South Asian (SAS)

AF:

0.380

AC:

1834

AN:

4826

European-Finnish (FIN)

AF:

0.169

AC:

1787

AN:

10576

Middle Eastern (MID)

AF:

0.312

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.157

AC:

10667

AN:

68012

Other (OTH)

AF:

0.276

AC:

583

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1379

2757

4136

5514

6893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.227

Hom.:

13804

Bravo

AF:

0.335

TwinsUK

AF:

0.146

AC:

543

ALSPAC

AF:

0.160

AC:

615

ESP6500AA

AF:

0.603

AC:

2656

ESP6500EA

AF:

0.155

AC:

1334

ExAC

AF:

0.275

AC:

33437

Asia WGS

AF:

0.506

AC:

1761

AN:

3478

EpiCase

AF:

0.161

EpiControl

AF:

0.167

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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. -

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

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

not provided

Benign:3

Jul 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 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

- -

Amyotrophic lateral sclerosis type 4

Benign:2

Jan 12, 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

Feb 08, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.059

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

1.5

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.11

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

.;N

PhyloP100

-0.72

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

N;N

REVEL

Benign

0.21

Sift

Benign

0.83

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.0

.;B

Vest4

0.022

MPC

0.073

ClinPred

0.0012

GERP RS

-8.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.016

gMVP

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over