rs882709

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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=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 id is 95659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132329619-G-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
SETX	NM_015046.7 linkuse as main transcript	c.1979C>G	p.Ala660Gly	missense_variant	10/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6 linkuse as main transcript	c.1979C>G	p.Ala660Gly	missense_variant	10/26	1	NM_015046.7	ENSP00000224140	P1	Q7Z333-1

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

GnomAD3 exomes

AF:

0.117

AC:

29433

AN:

250562

Hom.:

3084

AF XY:

0.114

AC XY:

15437

AN XY:

135416

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 SAS exome

AF:

0.144

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

Gnomad4 AFR exome

AF:

0.236

Gnomad4 AMR exome

AF:

0.0930

Gnomad4 ASJ exome

AF:

0.0897

Gnomad4 EAS exome

AF:

0.418

Gnomad4 SAS exome

AF:

0.142

Gnomad4 FIN exome

AF:

0.0667

Gnomad4 NFE exome

AF:

0.0575

Gnomad4 OTH exome

AF:

0.104

GnomAD4 genome

AF:

0.125

AC:

19025

AN:

152168

Hom.:

1853

Cov.:

AF XY:

0.127

AC XY:

9435

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.228

Gnomad4 AMR

AF:

0.0867

Gnomad4 ASJ

AF:

0.0936

Gnomad4 EAS

AF:

0.422

Gnomad4 SAS

AF:

0.162

Gnomad4 FIN

AF:

0.0596

Gnomad4 NFE

AF:

0.0591

Gnomad4 OTH

AF:

0.104

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2012	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2017	- -

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 12, 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. -

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 12, 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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

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

MutationTaster

Benign

1.0

P;P;P

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

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