rs3831154

Positions:

• chr9-132298067-C-CA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_015046.7(SETX):​c.5781+12_5781+13insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,582,696 control chromosomes in the GnomAD database, including 41,346 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6056 hom., cov: 26)
  • Exomes 𝑓: 0.19 (35290 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0720

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 -16 ACMG points.

• BP6: Variant 9-132298067-C-CA is Benign according to our data. Variant chr9-132298067-C-CA is described in ClinVar as [Benign]. Clinvar id is 95666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.5781+12_5781+13insT		intron_variant		ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.5781+12_5781+13insT		intron_variant		1	NM_015046.7	ENSP00000224140	P1
SETX	ENST00000436441.5	c.507+12_507+13insT		intron_variant		5		ENSP00000409143

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37990 AN: 151828 Hom.: 6044 Cov.: 26

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.228

GnomAD3 exomes AF: 0.248 AC: 62201 AN: 251208 Hom.: 10521 AF XY: 0.247 AC XY: 33593 AN XY: 135804

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.689

Gnomad SAS exome AF: 0.364

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.192 AC: 274300 AN: 1430748 Hom.: 35290 Cov.: 28 AF XY: 0.196 AC XY: 140165 AN XY: 713828

Gnomad4 AFR exome AF: 0.392

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.706

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.228

GnomAD4 genome AF: 0.250 AC: 38040 AN: 151948 Hom.: 6056 Cov.: 26 AF XY: 0.256 AC XY: 19006 AN XY: 74266

Gnomad4 AFR AF: 0.382

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.379

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.230

Alfa AF: 0.199 Hom.: 785

Bravo AF: 0.258

Asia WGS AF: 0.490 AC: 1704 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	Jun 14, 2016	- -

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

- -

Amyotrophic lateral sclerosis type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Amyotrophic Lateral Sclerosis, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs3831154; hg19: chr9-135173454;