rs9411449

Positions:

• chr9-132331073-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.1077T>C​(p.Tyr359=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 1,611,662 control chromosomes in the GnomAD database, including 531,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (44091 hom., cov: 32)
  • Exomes 𝑓: 0.81 (487094 hom.)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.351

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=-0.78).
• BP6: Variant 9-132331073-A-G is Benign according to our data. Variant chr9-132331073-A-G is described in ClinVar as [Benign]. Clinvar id is 95658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132331073-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.351 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.1077T>C	p.Tyr359=	synonymous_variant	9/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.1077T>C	p.Tyr359=	synonymous_variant	9/26	1	NM_015046.7	ENSP00000224140	P1

Frequencies

GnomAD3 genomes AF: 0.750 AC: 114024 AN: 151968 Hom.: 44069 Cov.: 32

Gnomad AFR AF: 0.619

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.845

Gnomad OTH AF: 0.771

GnomAD3 exomes AF: 0.752 AC: 188932 AN: 251112 Hom.: 73942 AF XY: 0.753 AC XY: 102175 AN XY: 135738

Gnomad AFR exome AF: 0.617

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.748

Gnomad EAS exome AF: 0.308

Gnomad SAS exome AF: 0.636

Gnomad FIN exome AF: 0.832

Gnomad NFE exome AF: 0.842

Gnomad OTH exome AF: 0.784

GnomAD4 exome AF: 0.810 AC: 1181901 AN: 1459576 Hom.: 487094 Cov.: 39 AF XY: 0.805 AC XY: 584694 AN XY: 726210

Gnomad4 AFR exome AF: 0.606

Gnomad4 AMR exome AF: 0.807

Gnomad4 ASJ exome AF: 0.747

Gnomad4 EAS exome AF: 0.317

Gnomad4 SAS exome AF: 0.638

Gnomad4 FIN exome AF: 0.832

Gnomad4 NFE exome AF: 0.850

Gnomad4 OTH exome AF: 0.772

GnomAD4 genome AF: 0.750 AC: 114096 AN: 152086 Hom.: 44091 Cov.: 32 AF XY: 0.744 AC XY: 55341 AN XY: 74338

Gnomad4 AFR AF: 0.618

Gnomad4 AMR AF: 0.808

Gnomad4 ASJ AF: 0.734

Gnomad4 EAS AF: 0.333

Gnomad4 SAS AF: 0.620

Gnomad4 FIN AF: 0.831

Gnomad4 NFE AF: 0.845

Gnomad4 OTH AF: 0.769

Alfa AF: 0.818 Hom.: 118252

Bravo AF: 0.742

Asia WGS AF: 0.507 AC: 1763 AN: 3478

EpiCase AF: 0.840

EpiControl AF: 0.834

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, 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: Frequency, 2 labs classify as benign/LB in clinvar -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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	Jul 15, 2021	- -
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	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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	-0.78
CADD	Benign	4.4
DANN	Benign	0.36

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: rs9411449; hg19: chr9-135206460; COSMIC: COSV56380923;