rs1183768

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.3754G>A(p.Gly1252Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 1,613,874 control chromosomes in the GnomAD database, including 520,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 38858 hom., cov: 31)

Exomes 𝑓: 0.80 ( 481992 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.508

Publications

42 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=8.695825E-7).

BP6

Variant 9-132327844-C-T is Benign according to our data. Variant chr9-132327844-C-T is described in ClinVar as Benign. ClinVar VariationId is 95662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.3754G>A	p.Gly1252Arg	missense_variant	Exon 10 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.3754G>A	p.Gly1252Arg	missense_variant	Exon 10 of 26	1	NM_015046.7	ENSP00000224140.5		Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.683

AC:

103831

AN:

151922

Hom.:

38853

Cov.:

show subpopulations

Gnomad AFR

AF:

0.385

Gnomad AMI

AF:

0.860

Gnomad AMR

AF:

0.787

Gnomad ASJ

AF:

0.734

Gnomad EAS

AF:

0.323

Gnomad SAS

AF:

0.620

Gnomad FIN

AF:

0.832

Gnomad MID

AF:

0.685

Gnomad NFE

AF:

0.844

Gnomad OTH

AF:

0.728

GnomAD2 exomes

AF:

0.734

AC:

184546

AN:

251284

AF XY:

0.740

show subpopulations

Gnomad AFR exome

AF:

0.374

Gnomad AMR exome

AF:

0.795

Gnomad ASJ exome

AF:

0.748

Gnomad EAS exome

AF:

0.305

Gnomad FIN exome

AF:

0.832

Gnomad NFE exome

AF:

0.842

Gnomad OTH exome

AF:

0.776

GnomAD4 exome

AF:

0.802

AC:

1172479

AN:

1461834

Hom.:

481992

Cov.:

AF XY:

0.798

AC XY:

580592

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.368

AC:

12328

AN:

33480

American (AMR)

AF:

0.794

AC:

35508

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.747

AC:

19517

AN:

26134

East Asian (EAS)

AF:

0.287

AC:

11406

AN:

39698

South Asian (SAS)

AF:

0.637

AC:

54983

AN:

86256

European-Finnish (FIN)

AF:

0.831

AC:

44406

AN:

53406

Middle Eastern (MID)

AF:

0.662

AC:

3816

AN:

5768

European-Non Finnish (NFE)

AF:

0.850

AC:

944827

AN:

1111972

Other (OTH)

AF:

0.756

AC:

45688

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

14138

28276

42415

56553

70691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20848

41696

62544

83392

104240

<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:

0.683

AC:

103853

AN:

152040

Hom.:

38858

Cov.:

AF XY:

0.681

AC XY:

50590

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.384

AC:

15921

AN:

41446

American (AMR)

AF:

0.787

AC:

11998

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.734

AC:

2550

AN:

3472

East Asian (EAS)

AF:

0.324

AC:

1671

AN:

5160

South Asian (SAS)

AF:

0.620

AC:

2987

AN:

4816

European-Finnish (FIN)

AF:

0.832

AC:

8798

AN:

10576

Middle Eastern (MID)

AF:

0.699

AC:

204

AN:

292

European-Non Finnish (NFE)

AF:

0.844

AC:

57410

AN:

68008

Other (OTH)

AF:

0.727

AC:

1533

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1356

2711

4067

5422

6778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.779

Hom.:

182779

Bravo

AF:

0.665

TwinsUK

AF:

0.855

AC:

3172

ALSPAC

AF:

0.842

AC:

3244

ESP6500AA

AF:

0.397

AC:

1747

ESP6500EA

AF:

0.845

AC:

7267

ExAC

AF:

0.725

AC:

88015

Asia WGS

AF:

0.492

AC:

1713

AN:

3478

EpiCase

AF:

0.840

EpiControl

AF:

0.834

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:11

Jul 24, 2013

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

- -

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: Frequency, 2 labs classify as benign/LB in clinvar -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

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. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 4

Benign:3

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Apr 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2021

Genome-Nilou Lab

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

0.25

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.16

Eigen

Benign

-0.098

Eigen_PC

Benign

-0.078

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.66

MetaRNN

Benign

8.7e-7

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.1

PhyloP100

0.51

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.63

REVEL

Benign

0.24

Sift

Benign

0.13

Sift4G

Benign

0.46

Polyphen

0.48

Vest4

0.28

MutPred

0.14

Gain of helix (P = 0.0696);

MPC

0.099

ClinPred

0.020

GERP RS

4.7

Varity_R

0.072

gMVP

0.14

Mutation Taster

=58/42

polymorphism

(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