rs1183768

chr9-132327844-C-T

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.3754G>A(p.Gly1252Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 1,613,874 control chromosomes in the GnomAD database, including 520,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (38858 hom., cov: 31)
  • Exomes 𝑓: 0.80 (481992 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.508

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=8.695825E-7).
• BP6: Variant 9-132327844-C-T is Benign according to our data. Variant chr9-132327844-C-T is described in ClinVar as [Benign]. Clinvar id is 95662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132327844-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.3754G>A	p.Gly1252Arg	missense_variant	10/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.3754G>A	p.Gly1252Arg	missense_variant	10/26	1	NM_015046.7	P1

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103831 AN: 151922 Hom.: 38853 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.860

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.832

Gnomad MID AF: 0.685

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.728

GnomAD3 exomes AF: 0.734 AC: 184546 AN: 251284 Hom.: 71620 AF XY: 0.740 AC XY: 100434 AN XY: 135802

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.748

Gnomad EAS exome AF: 0.305

Gnomad SAS exome AF: 0.635

Gnomad FIN exome AF: 0.832

Gnomad NFE exome AF: 0.842

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.802 AC: 1172479 AN: 1461834 Hom.: 481992 Cov.: 70 AF XY: 0.798 AC XY: 580592 AN XY: 727216

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.794

Gnomad4 ASJ exome AF: 0.747

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.637

Gnomad4 FIN exome AF: 0.831

Gnomad4 NFE exome AF: 0.850

Gnomad4 OTH exome AF: 0.756

GnomAD4 genome AF: 0.683 AC: 103853 AN: 152040 Hom.: 38858 Cov.: 31 AF XY: 0.681 AC XY: 50590 AN XY: 74300

Gnomad4 AFR AF: 0.384

Gnomad4 AMR AF: 0.787

Gnomad4 ASJ AF: 0.734

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.620

Gnomad4 FIN AF: 0.832

Gnomad4 NFE AF: 0.844

Gnomad4 OTH AF: 0.727

Alfa AF: 0.800 Hom.: 127467

Bravo AF: 0.665

TwinsUK AF: 0.855 AC: 3172

ALSPAC AF: 0.842 AC: 3244

ESP6500AA AF: 0.397 AC: 1747

ESP6500EA AF: 0.845 AC: 7267

ExAC AF: 0.725 AC: 88015

Asia WGS AF: 0.492 AC: 1713 AN: 3478

EpiCase AF: 0.840

EpiControl AF: 0.834

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:11

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2013	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Amyotrophic lateral sclerosis type 4 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 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. -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 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 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.38	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.24
Sift	Benign	0.13	T
Sift4G	Benign	0.46	T
Polyphen		0.48	P
Vest4		0.28
MutPred		0.14		Gain of helix (P = 0.0696);
MPC		0.099
ClinPred		0.020	T
GERP RS		4.7
Varity_R		0.072
gMVP		0.14

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: rs1183768; hg19: chr9-135203231; COSMIC: COSV56379133;