rs1185193

Positions:

Variant summary

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

The ENST00000224140.6(SETX):c.3576T>G(p.Asp1192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 1,613,658 control chromosomes in the GnomAD database, including 550,679 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 0.77 ( 46132 hom., cov: 31)

Exomes 𝑓: 0.82 ( 504547 hom. )

Consequence

SETX
ENST00000224140.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -1.15

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=8.1617526E-7).

BP6

Variant 9-132328022-A-C is Benign according to our data. Variant chr9-132328022-A-C is described in ClinVar as [Benign]. Clinvar id is 95661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132328022-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.854 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.3576T>G	p.Asp1192Glu	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.3576T>G	p.Asp1192Glu	missense_variant	10/26	1	NM_015046.7	ENSP00000224140	P1	Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.768

AC:

116730

AN:

151978

Hom.:

46110

Cov.:

show subpopulations

Gnomad AFR

AF:

0.643

Gnomad AMI

AF:

0.875

Gnomad AMR

AF:

0.817

Gnomad ASJ

AF:

0.768

Gnomad EAS

AF:

0.330

Gnomad SAS

AF:

0.636

Gnomad FIN

AF:

0.858

Gnomad MID

AF:

0.712

Gnomad NFE

AF:

0.860

Gnomad OTH

AF:

0.788

GnomAD3 exomes

AF:

0.768

AC:

192797

AN:

251086

Hom.:

76930

AF XY:

0.768

AC XY:

104256

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.642

Gnomad AMR exome

AF:

0.812

Gnomad ASJ exome

AF:

0.783

Gnomad EAS exome

AF:

0.313

Gnomad SAS exome

AF:

0.654

Gnomad FIN exome

AF:

0.857

Gnomad NFE exome

AF:

0.857

Gnomad OTH exome

AF:

0.800

GnomAD4 exome

AF:

0.823

AC:

1203440

AN:

1461562

Hom.:

504547

Cov.:

AF XY:

0.819

AC XY:

595396

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.631

Gnomad4 AMR exome

AF:

0.813

Gnomad4 ASJ exome

AF:

0.781

Gnomad4 EAS exome

AF:

0.295

Gnomad4 SAS exome

AF:

0.656

Gnomad4 FIN exome

AF:

0.856

Gnomad4 NFE exome

AF:

0.864

Gnomad4 OTH exome

AF:

0.787

GnomAD4 genome

AF:

0.768

AC:

116803

AN:

152096

Hom.:

46132

Cov.:

AF XY:

0.763

AC XY:

56734

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.643

Gnomad4 AMR

AF:

0.817

Gnomad4 ASJ

AF:

0.768

Gnomad4 EAS

AF:

0.331

Gnomad4 SAS

AF:

0.636

Gnomad4 FIN

AF:

0.858

Gnomad4 NFE

AF:

0.860

Gnomad4 OTH

AF:

0.786

Alfa

AF:

0.826

Hom.:

125056

Bravo

AF:

0.758

TwinsUK

AF:

0.866

AC:

3211

ALSPAC

AF:

0.856

AC:

3299

ESP6500AA

AF:

0.659

AC:

2902

ESP6500EA

AF:

0.862

AC:

7411

ExAC

AF:

0.763

AC:

92682

Asia WGS

AF:

0.516

AC:

1796

AN:

3478

EpiCase

AF:

0.856

EpiControl

AF:

0.849

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

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, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, 2 labs classify as benign/LB in clinvar -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:3

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	Athena Diagnostics	Apr 12, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Amyotrophic lateral sclerosis type 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.0010

DANN

Benign

0.74

DEOGEN2

Benign

0.11

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.15

MetaRNN

Benign

8.2e-7

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.64

REVEL

Benign

0.27

Sift

Benign

0.38

Sift4G

Benign

0.46

Polyphen

0.0010

Vest4

0.010

MutPred

0.049

Gain of methylation at K1190 (P = 0.0802);

MPC

0.070

ClinPred

0.020

GERP RS

-9.5

Varity_R

0.071

gMVP

0.060

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