9-132264439-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.7834A>G(p.Ser2612Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0525 in 1,609,902 control chromosomes in the GnomAD database, including 6,176 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 0.087 ( 1076 hom., cov: 31)

Exomes 𝑓: 0.049 ( 5100 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.45

Publications

21 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=0.002356708).

BP6

Variant 9-132264439-T-C is Benign according to our data. Variant chr9-132264439-T-C is described in ClinVar as Benign. ClinVar VariationId is 195975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.7834A>G	p.Ser2612Gly	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.7834A>G	p.Ser2612Gly	missense_variant	Exon 26 of 26	1	NM_015046.7	ENSP00000224140.5	Q7Z333-1
SETX	ENST00000436441.5 link	c.2647A>G	p.Ser883Gly	missense_variant	Exon 17 of 17	5		ENSP00000409143.1	X6RI79
SETX	ENST00000477049.1 link	n.984A>G		non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0870

AC:

13180

AN:

151436

Hom.:

1070

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.0740

Gnomad ASJ

AF:

0.0519

Gnomad EAS

AF:

0.377

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.0476

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0273

Gnomad OTH

AF:

0.0770

GnomAD2 exomes

AF:

0.0854

AC:

21453

AN:

251308

AF XY:

0.0811

show subpopulations

Gnomad AFR exome

AF:

0.166

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.0483

Gnomad EAS exome

AF:

0.386

Gnomad FIN exome

AF:

0.0446

Gnomad NFE exome

AF:

0.0268

Gnomad OTH exome

AF:

0.0637

GnomAD4 exome

AF:

0.0489

AC:

71257

AN:

1458338

Hom.:

5100

Cov.:

AF XY:

0.0497

AC XY:

36087

AN XY:

725638

show subpopulations

African (AFR)

AF:

0.171

AC:

5698

AN:

33374

American (AMR)

AF:

0.0991

AC:

4425

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0488

AC:

1269

AN:

25982

East Asian (EAS)

AF:

0.394

AC:

15577

AN:

39564

South Asian (SAS)

AF:

0.105

AC:

9018

AN:

86236

European-Finnish (FIN)

AF:

0.0455

AC:

2398

AN:

52750

Middle Eastern (MID)

AF:

0.0826

AC:

474

AN:

5740

European-Non Finnish (NFE)

AF:

0.0253

AC:

28034

AN:

1109922

Other (OTH)

AF:

0.0726

AC:

4364

AN:

60122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

4630

9260

13891

18521

23151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1440

2880

4320

5760

7200

<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:

0.0872

AC:

13213

AN:

151564

Hom.:

1076

Cov.:

AF XY:

0.0905

AC XY:

6704

AN XY:

74092

show subpopulations

African (AFR)

AF:

0.164

AC:

6798

AN:

41350

American (AMR)

AF:

0.0747

AC:

1135

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.0519

AC:

180

AN:

3470

East Asian (EAS)

AF:

0.377

AC:

1910

AN:

5072

South Asian (SAS)

AF:

0.129

AC:

607

AN:

4708

European-Finnish (FIN)

AF:

0.0476

AC:

503

AN:

10572

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0273

AC:

1851

AN:

67882

Other (OTH)

AF:

0.0805

AC:

170

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

543

1087

1630

2174

2717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0518

Hom.:

2526

Bravo

AF:

0.0950

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.165

AC:

725

ESP6500EA

AF:

0.0260

AC:

224

ExAC

AF:

0.0851

AC:

10335

Asia WGS

AF:

0.253

AC:

878

AN:

3478

EpiCase

AF:

0.0308

EpiControl

AF:

0.0314

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Dec 17, 2014

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

- -

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

- -

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, 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

- -

not provided

Benign:3

Apr 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 20, 2018

GeneDx

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

0.061

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.52

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.093

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.93

.;L

PhyloP100

-1.4

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.21

Sift

Benign

0.65

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.0

.;B

Vest4

0.0070

MPC

0.069

ClinPred

0.00059

GERP RS

-4.6

Varity_R

0.016

gMVP

0.12

Mutation Taster

=99/1

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