9-132311741-G-A

Variant names:

• chr9-132311741-G-A
• rs2296872
• NM_015046.7:c.5374+16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015046.7(SETX):​c.5374+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,546,828 control chromosomes in the GnomAD database, including 40,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6086 hom., cov: 32)
  • Exomes 𝑓: 0.19 (34827 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.83
• Publications: 6 publications found

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]

SETX Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• distal hereditary motor neuropathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 9-132311741-G-A is Benign according to our data. Variant chr9-132311741-G-A is described in ClinVar as Benign. ClinVar VariationId is 95664.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015046.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	NM_015046.7	MANE Select	c.5374+16C>T		intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.5374+16C>T		intron	N/A	NP_001338457.1
	SETX	NM_001351527.2		c.5374+16C>T		intron	N/A	NP_001338456.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.5374+16C>T		intron	N/A	ENSP00000224140.5
	SETX	ENST00000436441.5	TSL:5	c.100+16C>T		intron	N/A	ENSP00000409143.1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38068 AN: 151780 Hom.: 6076 Cov.: 32

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.227

GnomAD2 exomes AF: 0.247 AC: 60988 AN: 246488 AF XY: 0.247

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.689

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.193 AC: 269797 AN: 1394930 Hom.: 34827 Cov.: 24 AF XY: 0.198 AC XY: 138087 AN XY: 697938

African (AFR) AF: 0.395 AC: 12645 AN: 32038

American (AMR) AF: 0.193 AC: 8594 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6484 AN: 25626

East Asian (EAS) AF: 0.707 AC: 27783 AN: 39316

South Asian (SAS) AF: 0.361 AC: 30559 AN: 84640

European-Finnish (FIN) AF: 0.168 AC: 8799 AN: 52432

Middle Eastern (MID) AF: 0.325 AC: 1753 AN: 5386

European-Non Finnish (NFE) AF: 0.152 AC: 159889 AN: 1052920

Other (OTH) AF: 0.229 AC: 13291 AN: 58126

GnomAD4 genome AF: 0.251 AC: 38115 AN: 151898 Hom.: 6086 Cov.: 32 AF XY: 0.256 AC XY: 19037 AN XY: 74254

African (AFR) AF: 0.383 AC: 15854 AN: 41370

American (AMR) AF: 0.191 AC: 2922 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 922 AN: 3468

East Asian (EAS) AF: 0.671 AC: 3476 AN: 5182

South Asian (SAS) AF: 0.379 AC: 1824 AN: 4810

European-Finnish (FIN) AF: 0.168 AC: 1775 AN: 10536

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.157 AC: 10642 AN: 67956

Other (OTH) AF: 0.229 AC: 483 AN: 2110

Alfa AF: 0.212 Hom.: 772

Bravo AF: 0.259

Asia WGS AF: 0.491 AC: 1706 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 14, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Amyotrophic lateral sclerosis type 4 Benign:1

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Benign:1

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.12
DANN	Benign	0.55
PhyloP100		-1.8
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2296872; hg19: chr9-135187128; COSMIC: COSV56391477;