9-132297025-A-G

Position:

• chr9-132297025-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015046.7(SETX):​c.5811T>C​(p.Asp1937=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,012 control chromosomes in the GnomAD database, including 51,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (11023 hom., cov: 32)
  • Exomes 𝑓: 0.20 (40460 hom.)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.690

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 9-132297025-A-G is Benign according to our data. Variant chr9-132297025-A-G is described in ClinVar as [Benign]. Clinvar id is 95667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132297025-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.5811T>C	p.Asp1937=	synonymous_variant	14/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.5811T>C	p.Asp1937=	synonymous_variant	14/26	1	NM_015046.7	ENSP00000224140	P1
SETX	ENST00000436441.5	c.537T>C	p.Asp179=	synonymous_variant	4/17	5		ENSP00000409143

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48155 AN: 151882 Hom.: 10981 Cov.: 32

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.274

GnomAD3 exomes AF: 0.265 AC: 66348 AN: 249954 Hom.: 12526 AF XY: 0.260 AC XY: 35190 AN XY: 135194

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.689

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: 290173 AN: 1460014 Hom.: 40460 Cov.: 32 AF XY: 0.202 AC XY: 147009 AN XY: 726382

Gnomad4 AFR exome AF: 0.632

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.706

Gnomad4 SAS exome AF: 0.362

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.317 AC: 48251 AN: 151998 Hom.: 11023 Cov.: 32 AF XY: 0.320 AC XY: 23733 AN XY: 74266

Gnomad4 AFR AF: 0.616

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.275

Alfa AF: 0.221 Hom.: 3899

Bravo AF: 0.335

Asia WGS AF: 0.503 AC: 1750 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Clinical Genetics, Academic 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, 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2012	- -
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 -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.0
DANN	Benign	0.46

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: rs2296869; hg19: chr9-135172412; COSMIC: COSV56380974;