9-132298298-T-C

Position:

• chr9-132298298-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.5563A>G​(p.Thr1855Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,270 control chromosomes in the GnomAD database, including 51,750 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1855P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.32 (11057 hom., cov: 33)
  • Exomes 𝑓: 0.20 (40693 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.716

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5498156E-6).
• BP6: Variant 9-132298298-T-C is Benign according to our data. Variant chr9-132298298-T-C is described in ClinVar as [Benign]. Clinvar id is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132298298-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.5563A>G	p.Thr1855Ala	missense_variant	13/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.5563A>G	p.Thr1855Ala	missense_variant	13/26	1	NM_015046.7	ENSP00000224140.5
SETX	ENST00000436441.5	c.289A>G	p.Thr97Ala	missense_variant	3/17	5		ENSP00000409143.1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48237 AN: 152030 Hom.: 11015 Cov.: 33

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.275

GnomAD3 exomes AF: 0.266 AC: 66814 AN: 251216 Hom.: 12717 AF XY: 0.261 AC XY: 35421 AN XY: 135794

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.695

Gnomad SAS exome AF: 0.364

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.199 AC: 290334 AN: 1460122 Hom.: 40693 Cov.: 33 AF XY: 0.203 AC XY: 147124 AN XY: 726470

Gnomad4 AFR exome AF: 0.632

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.713

Gnomad4 SAS exome AF: 0.362

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.318 AC: 48333 AN: 152148 Hom.: 11057 Cov.: 33 AF XY: 0.320 AC XY: 23801 AN XY: 74376

Gnomad4 AFR AF: 0.616

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.676

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.276

Alfa AF: 0.207 Hom.: 8232

Bravo AF: 0.335

TwinsUK AF: 0.146 AC: 543

ALSPAC AF: 0.160 AC: 615

ESP6500AA AF: 0.603 AC: 2656

ESP6500EA AF: 0.155 AC: 1334

ExAC AF: 0.275 AC: 33437

Asia WGS AF: 0.506 AC: 1761 AN: 3478

EpiCase AF: 0.161

EpiControl AF: 0.167

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2012	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	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	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	GeneDx	Jul 03, 2018	- -
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	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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.5
DANN	Benign	0.30
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.11	T;T
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	.;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.0	N;N
REVEL	Benign	0.21
Sift	Benign	0.83	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0	.;B
Vest4		0.022
MPC		0.073
ClinPred		0.0012	T
GERP RS		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.21

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: rs2296871; hg19: chr9-135173685; COSMIC: COSV56380996;