9-132328623-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015046.7(SETX):c.2975A>G(p.Lys992Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,490 control chromosomes in the GnomAD database, including 252 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K992Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 33)

Exomes 𝑓: 0.015 ( 229 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 1.08

Publications

17 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022610426).

BP6

Variant 9-132328623-T-C is Benign according to our data. Variant chr9-132328623-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260502.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0141 (2151/152308) while in subpopulation NFE AF = 0.0175 (1189/68026). AF 95% confidence interval is 0.0167. There are 23 homozygotes in GnomAd4. There are 1102 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.2975A>G	p.Lys992Arg	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.2975A>G	p.Lys992Arg	missense_variant	Exon 10 of 26	1	NM_015046.7	ENSP00000224140.5		Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2155

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.0505

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0152

AC:

3812

AN:

250468

AF XY:

0.0160

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.00778

Gnomad ASJ exome

AF:

0.00747

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0505

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0154

GnomAD4 exome

AF:

0.0145

AC:

21237

AN:

1461182

Hom.:

229

Cov.:

AF XY:

0.0148

AC XY:

10739

AN XY:

726898

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

33434

American (AMR)

AF:

0.00823

AC:

367

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00732

AC:

191

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00705

AC:

607

AN:

86158

European-Finnish (FIN)

AF:

0.0468

AC:

2497

AN:

53362

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0150

AC:

16621

AN:

1111706

Other (OTH)

AF:

0.0133

AC:

801

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1238

2476

3715

4953

6191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

564

1128

1692

2256

2820

<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:

0.0141

AC:

2151

AN:

152308

Hom.:

Cov.:

AF XY:

0.0148

AC XY:

1102

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00257

AC:

107

AN:

41576

American (AMR)

AF:

0.0142

AC:

217

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00601

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0505

AC:

535

AN:

10594

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0175

AC:

1189

AN:

68026

Other (OTH)

AF:

0.0170

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

100

200

299

399

499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0145

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0163

AC:

140

ExAC

AF:

0.0151

AC:

1828

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

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, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 05, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SETX: BP4, BS1, BS2 -

Nov 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28430856, 27884173, 17159128, 23941260, 23129421, 20981092, 24083349, 23881933) -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Spastic paraplegia

Uncertain:1

Paris Brain Institute, Inserm - ICM

Significance:Uncertain significance

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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Jul 08, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 4

Benign:1

Mar 06, 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. -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

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

0.081

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.4

PhyloP100

1.1

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

REVEL

Benign

0.24

Sift

Benign

0.039

Sift4G

Benign

0.081

Polyphen

0.034

Vest4

0.030

MPC

0.072

ClinPred

0.00094

GERP RS

0.24

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.094

gMVP

0.24

Mutation Taster

=88/12

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