NM_015046.7:c.1979C>G

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.1979C>G(p.Ala660Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0848 in 1,613,224 control chromosomes in the GnomAD database, including 10,094 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 0.13 ( 1853 hom., cov: 33)

Exomes 𝑓: 0.081 ( 8241 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.27

Publications

37 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=3.9163232E-4).

BP6

Variant 9-132329619-G-C is Benign according to our data. Variant chr9-132329619-G-C is described in ClinVar as Benign. ClinVar VariationId is 95659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.1979C>G	p.Ala660Gly	missense_variant	Exon 10 of 26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6 link	c.1979C>G	p.Ala660Gly	missense_variant	Exon 10 of 26	1	NM_015046.7	ENSP00000224140.5

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

19006

AN:

152050

Hom.:

1853

Cov.:

show subpopulations

Gnomad AFR

AF:

0.228

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0866

Gnomad ASJ

AF:

0.0936

Gnomad EAS

AF:

0.423

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.0596

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.0591

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.117

AC:

29433

AN:

250562

AF XY:

0.114

show subpopulations

Gnomad AFR exome

AF:

0.230

Gnomad AMR exome

AF:

0.0951

Gnomad ASJ exome

AF:

0.0869

Gnomad EAS exome

AF:

0.448

Gnomad FIN exome

AF:

0.0682

Gnomad NFE exome

AF:

0.0609

Gnomad OTH exome

AF:

0.0921

GnomAD4 exome

AF:

0.0806

AC:

117728

AN:

1461056

Hom.:

8241

Cov.:

AF XY:

0.0816

AC XY:

59300

AN XY:

726822

show subpopulations

African (AFR)

AF:

0.236

AC:

7905

AN:

33426

American (AMR)

AF:

0.0930

AC:

4155

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0897

AC:

2343

AN:

26120

East Asian (EAS)

AF:

0.418

AC:

16599

AN:

39676

South Asian (SAS)

AF:

0.142

AC:

12253

AN:

86182

European-Finnish (FIN)

AF:

0.0667

AC:

3549

AN:

53216

Middle Eastern (MID)

AF:

0.123

AC:

709

AN:

5766

European-Non Finnish (NFE)

AF:

0.0575

AC:

63943

AN:

1111616

Other (OTH)

AF:

0.104

AC:

6272

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

5350

10700

16051

21401

26751

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2770

5540

8310

11080

13850

<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:

0.125

AC:

19025

AN:

152168

Hom.:

1853

Cov.:

AF XY:

0.127

AC XY:

9435

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.228

AC:

9462

AN:

41514

American (AMR)

AF:

0.0867

AC:

1325

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0936

AC:

325

AN:

3472

East Asian (EAS)

AF:

0.422

AC:

2185

AN:

5176

South Asian (SAS)

AF:

0.162

AC:

779

AN:

4820

European-Finnish (FIN)

AF:

0.0596

AC:

632

AN:

10596

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0591

AC:

4017

AN:

67992

Other (OTH)

AF:

0.104

AC:

219

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

809

1618

2428

3237

4046

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<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:

0.0779

Hom.:

222

Bravo

AF:

0.134

TwinsUK

AF:

0.0572

AC:

212

ALSPAC

AF:

0.0579

AC:

223

ESP6500AA

AF:

0.223

AC:

982

ESP6500EA

AF:

0.0579

AC:

498

ExAC

AF:

0.121

AC:

14697

Asia WGS

AF:

0.281

AC:

978

AN:

3478

EpiCase

AF:

0.0599

EpiControl

AF:

0.0621

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

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

- -

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

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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 11, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Jan 12, 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

- -

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

Benign:1

Jan 31, 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

0.099

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.18

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.68

MetaRNN

Benign

0.00039

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

1.3

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.0

REVEL

Benign

0.22

Sift

Uncertain

0.0080

Sift4G

Benign

0.17

Polyphen

0.42

Vest4

0.055

MPC

0.13

ClinPred

0.0020

GERP RS

2.1

Varity_R

0.048

gMVP

0.13

Mutation Taster

=97/3

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