rs151117904

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.7640T>C(p.Ile2547Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,614,206 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 25 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.238

Publications

28 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=0.0033735633).

BP6

Variant 9-132264633-A-G is Benign according to our data. Variant chr9-132264633-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 155748.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00428 (652/152312) while in subpopulation AMR AF = 0.0122 (186/15300). AF 95% confidence interval is 0.0107. There are 4 homozygotes in GnomAd4. There are 310 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.7640T>C	p.Ile2547Thr	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.7640T>C	p.Ile2547Thr	missense_variant	Exon 26 of 26	1	NM_015046.7	ENSP00000224140.5	Q7Z333-1
SETX	ENST00000436441.5 link	c.2453T>C	p.Ile818Thr	missense_variant	Exon 17 of 17	5		ENSP00000409143.1	X6RI79
SETX	ENST00000477049.1 link	n.790T>C		non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.00428

AC:

652

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00550

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00391

AC:

983

AN:

251496

AF XY:

0.00386

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00572

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.00518

AC:

7573

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

3722

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

33480

American (AMR)

AF:

0.00691

AC:

309

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00122

AC:

105

AN:

86258

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00602

AC:

6698

AN:

1112012

Other (OTH)

AF:

0.00536

AC:

324

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

523

1046

1569

2092

2615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

248

496

744

992

1240

<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:

0.00428

AC:

652

AN:

152312

Hom.:

Cov.:

AF XY:

0.00416

AC XY:

310

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41554

American (AMR)

AF:

0.0122

AC:

186

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00550

AC:

374

AN:

68032

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00496

Hom.:

Bravo

AF:

0.00532

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00342

AC:

415

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00581

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:8

Apr 15, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25802885, 23129421, 22088787, 29080331, 21438761, 21190393, 27884173, 23447461, 25382069, 28430856) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Northcott Neuroscience Laboratory, ANZAC Research Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SETX: BP4, BS2 -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 08, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis

Uncertain:1

Sep 09, 2020

UM ALS/MND Lab, University Of Malta

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:case-control

- -

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

- -

Hereditary spastic paraplegia

Benign:1

May 12, 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.70

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.093

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.32

T;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.0

.;N

PhyloP100

0.24

PrimateAI

Benign

0.27

PROVEAN

Benign

0.42

N;N

REVEL

Benign

0.11

Sift

Benign

0.32

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0

.;B

Vest4

0.044

MVP

0.43

MPC

0.093

ClinPred

0.00057

GERP RS

-3.4

Varity_R

0.017

gMVP

0.12

Mutation Taster

=99/1

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