rs79740039

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015046.7(SETX):c.59G>A(p.Arg20His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00853 in 1,614,102 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0064 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 89 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.510

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=0.004255116).

BP6

Variant 9-132349370-C-T is Benign according to our data. Variant chr9-132349370-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 242635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132349370-C-T is described in Lovd as [Benign]. Variant chr9-132349370-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00636 (968/152210) while in subpopulation SAS AF= 0.0153 (74/4824). AF 95% confidence interval is 0.0125. There are 5 homozygotes in gnomad4. There are 496 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7 linkuse as main transcript	c.59G>A	p.Arg20His	missense_variant	3/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6 linkuse as main transcript	c.59G>A	p.Arg20His	missense_variant	3/26	1	NM_015046.7	P1	Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.00636

AC:

968

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0153

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00842

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00924

AC:

2325

AN:

251488

Hom.:

AF XY:

0.00978

AC XY:

1329

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00393

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0172

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.00944

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.00875

AC:

12794

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00912

AC XY:

6633

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00420

Gnomad4 ASJ exome

AF:

0.0148

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0171

Gnomad4 FIN exome

AF:

0.0148

Gnomad4 NFE exome

AF:

0.00839

Gnomad4 OTH exome

AF:

0.00886

GnomAD4 genome

AF:

0.00636

AC:

968

AN:

152210

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

496

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00399

Gnomad4 ASJ

AF:

0.0187

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0153

Gnomad4 FIN

AF:

0.0122

Gnomad4 NFE

AF:

0.00842

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00816

Hom.:

Bravo

AF:

0.00535

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00906

AC:

1100

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00878

EpiControl

AF:

0.00936

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SETX: BP4, BS1, BS2 -

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

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Amyotrophic lateral sclerosis type 4

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 29, 2021

- -

SETX-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

Cadd

Benign

6.6

Dann

Benign

0.92

DEOGEN2

Benign

0.12

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.20

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.29

REVEL

Benign

0.16

Sift

Benign

0.17

Sift4G

Benign

0.15

Polyphen

0.0010

Vest4

0.15

MVP

0.45

MPC

0.092

ClinPred

0.0012

GERP RS

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.014

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