9-132264439-T-C

Position:

chr9-132264439-T-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.7834A>G(p.Ser2612Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0525 in 1,609,902 control chromosomes in the GnomAD database, including 6,176 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 0.087 ( 1076 hom., cov: 31)

Exomes 𝑓: 0.049 ( 5100 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -1.45

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=0.002356708).

BP6

Variant 9-132264439-T-C is Benign according to our data. Variant chr9-132264439-T-C is described in ClinVar as [Benign]. Clinvar id is 195975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132264439-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 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.7834A>G	p.Ser2612Gly	missense_variant	26/26	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.7834A>G	p.Ser2612Gly	missense_variant	26/26	1	NM_015046.7	ENSP00000224140	P1	Q7Z333-1
SETX	ENST00000436441.5 linkuse as main transcript	c.2647A>G	p.Ser883Gly	missense_variant	17/17	5		ENSP00000409143
SETX	ENST00000477049.1 linkuse as main transcript	n.984A>G		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.0870

AC:

13180

AN:

151436

Hom.:

1070

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.0740

Gnomad ASJ

AF:

0.0519

Gnomad EAS

AF:

0.377

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.0476

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0273

Gnomad OTH

AF:

0.0770

GnomAD3 exomes

AF:

0.0854

AC:

21453

AN:

251308

Hom.:

2061

AF XY:

0.0811

AC XY:

11018

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.166

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.0483

Gnomad EAS exome

AF:

0.386

Gnomad SAS exome

AF:

0.107

Gnomad FIN exome

AF:

0.0446

Gnomad NFE exome

AF:

0.0268

Gnomad OTH exome

AF:

0.0637

GnomAD4 exome

AF:

0.0489

AC:

71257

AN:

1458338

Hom.:

5100

Cov.:

AF XY:

0.0497

AC XY:

36087

AN XY:

725638

show subpopulations

Gnomad4 AFR exome

AF:

0.171

Gnomad4 AMR exome

AF:

0.0991

Gnomad4 ASJ exome

AF:

0.0488

Gnomad4 EAS exome

AF:

0.394

Gnomad4 SAS exome

AF:

0.105

Gnomad4 FIN exome

AF:

0.0455

Gnomad4 NFE exome

AF:

0.0253

Gnomad4 OTH exome

AF:

0.0726

GnomAD4 genome

AF:

0.0872

AC:

13213

AN:

151564

Hom.:

1076

Cov.:

AF XY:

0.0905

AC XY:

6704

AN XY:

74092

show subpopulations

Gnomad4 AFR

AF:

0.164

Gnomad4 AMR

AF:

0.0747

Gnomad4 ASJ

AF:

0.0519

Gnomad4 EAS

AF:

0.377

Gnomad4 SAS

AF:

0.129

Gnomad4 FIN

AF:

0.0476

Gnomad4 NFE

AF:

0.0273

Gnomad4 OTH

AF:

0.0805

Alfa

AF:

0.0471

Hom.:

1158

Bravo

AF:

0.0950

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.165

AC:

725

ESP6500EA

AF:

0.0260

AC:

224

ExAC

AF:

0.0851

AC:

10335

Asia WGS

AF:

0.253

AC:

878

AN:

3478

EpiCase

AF:

0.0308

EpiControl

AF:

0.0314

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, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	- -
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	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

0.061

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.52

DANN

Benign

0.70

DEOGEN2

Benign

0.093

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.93

.;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.21

Sift

Benign

0.65

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.0

.;B

Vest4

0.0070

MPC

0.069

ClinPred

0.00059

GERP RS

-4.6

Varity_R

0.016

gMVP

0.12

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