9-132264514-T-C

Position:

• chr9-132264514-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015046.7(SETX):​c.7759A>G​(p.Ile2587Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,704 control chromosomes in the GnomAD database, including 103,719 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 0.44 (18120 hom., cov: 31)
  • Exomes 𝑓: 0.32 (85599 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.19

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2665112E-6).
• BP6: Variant 9-132264514-T-C is Benign according to our data. Variant chr9-132264514-T-C is described in ClinVar as [Benign]. Clinvar id is 95669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132264514-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.7759A>G	p.Ile2587Val	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	c.7759A>G	p.Ile2587Val	missense_variant	26/26	1	NM_015046.7	ENSP00000224140.5
SETX	ENST00000436441.5	c.2572A>G	p.Ile858Val	missense_variant	17/17	5		ENSP00000409143.1
SETX	ENST00000477049.1	n.909A>G		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67461 AN: 151896 Hom.: 18073 Cov.: 31

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.418

GnomAD3 exomes AF: 0.383 AC: 96108 AN: 251178 Hom.: 21414 AF XY: 0.378 AC XY: 51299 AN XY: 135786

Gnomad AFR exome AF: 0.756

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.727

Gnomad SAS exome AF: 0.441

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.323 AC: 471972 AN: 1461690 Hom.: 85599 Cov.: 59 AF XY: 0.326 AC XY: 237034 AN XY: 727140

Gnomad4 AFR exome AF: 0.763

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.385

Gnomad4 EAS exome AF: 0.737

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.372

GnomAD4 genome AF: 0.444 AC: 67565 AN: 152014 Hom.: 18120 Cov.: 31 AF XY: 0.444 AC XY: 32992 AN XY: 74304

Gnomad4 AFR AF: 0.746

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.714

Gnomad4 SAS AF: 0.453

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.416

Alfa AF: 0.331 Hom.: 24228

Bravo AF: 0.465

TwinsUK AF: 0.274 AC: 1017

ALSPAC AF: 0.284 AC: 1095

ESP6500AA AF: 0.732 AC: 3227

ESP6500EA AF: 0.297 AC: 2550

ExAC AF: 0.392 AC: 47626

Asia WGS AF: 0.576 AC: 2005 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.307

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:11

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: MAF -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2012	- -
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, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2015	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. -
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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	Feb 08, 2023	- -

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	0.068
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.0060
DANN	Benign	0.20
DEOGEN2	Benign	0.088	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.12	T;T
MetaRNN	Benign	0.0000013	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.55	.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.22	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.0040
MPC		0.063
ClinPred		0.0010	T
GERP RS		-3.8
Varity_R		0.014
gMVP		0.072

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

Other links and lift over

dbSNP: rs1056899; hg19: chr9-135139901; COSMIC: COSV56380941;