rs17148873

Variant names:

• chr9-132277052-A-G
• rs17148873
• NM_015046.7:c.6935+8T>C

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.6935+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0867 in 1,609,646 control chromosomes in the GnomAD database, including 6,849 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (759 hom., cov: 32)
  • Exomes 𝑓: 0.086 (6090 hom.)
• Consequence: SETX NM_015046.7 splice_region, intron
• Scores: Splicing: ADA: 0.0001784
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.447

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 (BayesDel_noAF=-0.8).
• BP6: Variant 9-132277052-A-G is Benign according to our data. Variant chr9-132277052-A-G is described in ClinVar as [Benign]. Clinvar id is 260514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132277052-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7	c.6935+8T>C		splice_region_variant, intron_variant	Intron 22 of 25	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.6935+8T>C		splice_region_variant, intron_variant	Intron 22 of 25	1	NM_015046.7	ENSP00000224140.5
SETX	ENST00000436441.5	c.1661+8T>C		splice_region_variant, intron_variant	Intron 12 of 16	5		ENSP00000409143.1
SETX	ENST00000464133.1	n.133+8T>C		splice_region_variant, intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0944 AC: 14362 AN: 152154 Hom.: 757 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0498

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0818

Gnomad OTH AF: 0.0960

GnomAD3 exomes AF: 0.0883 AC: 22174 AN: 251174 Hom.: 1192 AF XY: 0.0934 AC XY: 12683 AN XY: 135758

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.0426

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.0429

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0846

Gnomad OTH exome AF: 0.0932

GnomAD4 exome AF: 0.0859 AC: 125233 AN: 1457376 Hom.: 6090 Cov.: 30 AF XY: 0.0889 AC XY: 64444 AN XY: 725290

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0456

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.0532

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.0740

Gnomad4 NFE exome AF: 0.0801

Gnomad4 OTH exome AF: 0.0935

GnomAD4 genome AF: 0.0944 AC: 14375 AN: 152270 Hom.: 759 Cov.: 32 AF XY: 0.0948 AC XY: 7062 AN XY: 74458

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.0699

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.0499

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.0682

Gnomad4 NFE AF: 0.0818

Gnomad4 OTH AF: 0.0945

Alfa AF: 0.0874 Hom.: 1288

Bravo AF: 0.0940

Asia WGS AF: 0.0940 AC: 328 AN: 3478

EpiCase AF: 0.0849

EpiControl AF: 0.0900

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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:3

Aug 10, 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

- -

Apr 11, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 4 Benign:2

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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;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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.7
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.014
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: rs17148873; hg19: chr9-135152439; COSMIC: COSV56392383; COSMIC: COSV56392383;