rs75682594

Variant names:

• chr9-132262539-C-A
• rs75682594
• NM_015046.7:c.*1700G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132262539-C-A
• chr9-132262539-C-G

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.*1700G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0469 in 152,500 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (534 hom., cov: 32)
  • Exomes 𝑓: 0.056 (1 hom.)
• Consequence: SETX NM_015046.7 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.328
• Publications: 2 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=-0.82).
• BP6: Variant 9-132262539-C-A is Benign according to our data. Variant chr9-132262539-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 365311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7	c.*1700G>T		3_prime_UTR_variant	Exon 26 of 26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.*1700G>T		3_prime_UTR_variant	Exon 26 of 26	1	NM_015046.7	ENSP00000224140.5
SETX	ENST00000477049.1	n.2884G>T		non_coding_transcript_exon_variant	Exon 5 of 5	3
SETX	ENST00000436441.5	c.*1700G>T		3_prime_UTR_variant	Exon 17 of 17	5		ENSP00000409143.1

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7126 AN: 152058 Hom.: 533 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0602

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0507

GnomAD4 exome AF: 0.0556 AC: 18 AN: 324 Hom.: 1 Cov.: 0 AF XY: 0.0333 AC XY: 6 AN XY: 180

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0634 AC: 18 AN: 284

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.0469 AC: 7137 AN: 152176 Hom.: 534 Cov.: 32 AF XY: 0.0508 AC XY: 3780 AN XY: 74406

African (AFR) AF: 0.0231 AC: 959 AN: 41528

American (AMR) AF: 0.0610 AC: 932 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3470

East Asian (EAS) AF: 0.377 AC: 1942 AN: 5152

South Asian (SAS) AF: 0.124 AC: 599 AN: 4826

European-Finnish (FIN) AF: 0.0475 AC: 504 AN: 10604

Middle Eastern (MID) AF: 0.0931 AC: 27 AN: 290

European-Non Finnish (NFE) AF: 0.0272 AC: 1851 AN: 68006

Other (OTH) AF: 0.0545 AC: 115 AN: 2112

Alfa AF: 0.0291 Hom.: 14

Bravo AF: 0.0480

Asia WGS AF: 0.248 AC: 860 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 4 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

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.0
DANN	Benign	0.66
PhyloP100		0.33
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: rs75682594; hg19: chr9-135137926;