rs3739921

chr9-132328451-G-A

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.3147C>T(p.His1049=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 1,613,326 control chromosomes in the GnomAD database, including 8,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (635 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7697 hom.)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.44

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=-0.84).
• BP6: Variant 9-132328451-G-A is Benign according to our data. Variant chr9-132328451-G-A is described in ClinVar as [Benign]. Clinvar id is 193716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132328451-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.3147C>T	p.His1049=	synonymous_variant	10/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.3147C>T	p.His1049=	synonymous_variant	10/26	1	NM_015046.7	P1

Frequencies

GnomAD3 genomes AF: 0.0817 AC: 12418 AN: 151908 Hom.: 637 Cov.: 32

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.0804

Gnomad AMR AF: 0.0849

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.0828

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0806

Gnomad OTH AF: 0.0901

GnomAD3 exomes AF: 0.108 AC: 27065 AN: 250960 Hom.: 1882 AF XY: 0.113 AC XY: 15300 AN XY: 135662

Gnomad AFR exome AF: 0.0406

Gnomad AMR exome AF: 0.0881

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.236

Gnomad SAS exome AF: 0.202

Gnomad FIN exome AF: 0.0741

Gnomad NFE exome AF: 0.0822

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0924 AC: 134961 AN: 1461300 Hom.: 7697 Cov.: 37 AF XY: 0.0962 AC XY: 69966 AN XY: 726964

Gnomad4 AFR exome AF: 0.0433

Gnomad4 AMR exome AF: 0.0885

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.257

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.0774

Gnomad4 NFE exome AF: 0.0786

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0818 AC: 12430 AN: 152026 Hom.: 635 Cov.: 32 AF XY: 0.0859 AC XY: 6378 AN XY: 74278

Gnomad4 AFR AF: 0.0434

Gnomad4 AMR AF: 0.0853

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.0828

Gnomad4 NFE AF: 0.0806

Gnomad4 OTH AF: 0.0920

Alfa AF: 0.0824 Hom.: 708

Bravo AF: 0.0801

Asia WGS AF: 0.193 AC: 670 AN: 3478

EpiCase AF: 0.0838

EpiControl AF: 0.0883

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -

Amyotrophic lateral sclerosis type 4 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	Feb 08, 2023	- -

not provided Benign:2

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

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	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

Invitae

Jan 31, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.37
Dann	Benign	0.29

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: rs3739921; hg19: chr9-135203838; COSMIC: COSV56383870;