rs3739922

Positions:

chr9-132328143-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015046.7(SETX):c.3455T>G(p.Phe1152Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,613,922 control chromosomes in the GnomAD database, including 2,842 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1152L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.050 ( 318 hom., cov: 32)

Exomes 𝑓: 0.045 ( 2524 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 1.30

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027791858).

BP6

Variant 9-132328143-A-C is Benign according to our data. Variant chr9-132328143-A-C is described in ClinVar as [Benign]. Clinvar id is 95660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132328143-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7 linkuse as main transcript	c.3455T>G	p.Phe1152Cys	missense_variant	10/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6 linkuse as main transcript	c.3455T>G	p.Phe1152Cys	missense_variant	10/26	1	NM_015046.7	P1	Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.0500

AC:

7611

AN:

152068

Hom.:

319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0503

Gnomad AMI

AF:

0.0352

Gnomad AMR

AF:

0.0474

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.256

Gnomad SAS

AF:

0.0734

Gnomad FIN

AF:

0.0480

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0347

Gnomad OTH

AF:

0.0412

GnomAD3 exomes

AF:

0.0652

AC:

16354

AN:

250992

Hom.:

997

AF XY:

0.0633

AC XY:

8585

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.0496

Gnomad AMR exome

AF:

0.0695

Gnomad ASJ exome

AF:

0.0331

Gnomad EAS exome

AF:

0.271

Gnomad SAS exome

AF:

0.0718

Gnomad FIN exome

AF:

0.0553

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0480

GnomAD4 exome

AF:

0.0451

AC:

65868

AN:

1461736

Hom.:

2524

Cov.:

AF XY:

0.0456

AC XY:

33123

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0482

Gnomad4 AMR exome

AF:

0.0662

Gnomad4 ASJ exome

AF:

0.0352

Gnomad4 EAS exome

AF:

0.247

Gnomad4 SAS exome

AF:

0.0710

Gnomad4 FIN exome

AF:

0.0538

Gnomad4 NFE exome

AF:

0.0345

Gnomad4 OTH exome

AF:

0.0486

GnomAD4 genome

AF:

0.0500

AC:

7615

AN:

152186

Hom.:

318

Cov.:

AF XY:

0.0514

AC XY:

3824

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0503

Gnomad4 AMR

AF:

0.0476

Gnomad4 ASJ

AF:

0.0351

Gnomad4 EAS

AF:

0.256

Gnomad4 SAS

AF:

0.0735

Gnomad4 FIN

AF:

0.0480

Gnomad4 NFE

AF:

0.0347

Gnomad4 OTH

AF:

0.0398

Alfa

AF:

0.0425

Hom.:

450

Bravo

AF:

0.0520

TwinsUK

AF:

0.0361

AC:

134

ALSPAC

AF:

0.0348

AC:

134

ESP6500AA

AF:

0.0479

AC:

211

ESP6500EA

AF:

0.0336

AC:

289

ExAC

AF:

0.0655

AC:

7958

Asia WGS

AF:

0.136

AC:

473

AN:

3478

EpiCase

AF:

0.0317

EpiControl

AF:

0.0325

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2012	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Amyotrophic lateral sclerosis type 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	This variant is associated with the following publications: (PMID: 24694197) -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.3

REVEL

Benign

0.25

Sift

Uncertain

0.0030

Sift4G

Benign

0.14

Polyphen

0.0030

Vest4

0.060

MPC

0.11

ClinPred

0.014

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.32

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over