9-132262539-C-A

Position:

• chr9-132262539-C-A

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.*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

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=-0.82).
• 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/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.*1700G>T		3_prime_UTR_variant	26/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.*1700G>T		3_prime_UTR_variant	26/26	1	NM_015046.7	ENSP00000224140	P1
SETX	ENST00000436441.5	c.*1700G>T		3_prime_UTR_variant	17/17	5		ENSP00000409143
SETX	ENST00000477049.1	n.2884G>T		non_coding_transcript_exon_variant	5/5	3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.0634

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.0610

Gnomad4 ASJ AF: 0.0519

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0475

Gnomad4 NFE AF: 0.0272

Gnomad4 OTH AF: 0.0545

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -

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	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.0
DANN	Benign	0.66

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: rs75682594; hg19: chr9-135137926;