9-132261977-T-C

Position:

• chr9-132261977-T-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.*2262A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0962 in 154,414 control chromosomes in the GnomAD database, including 818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (763 hom., cov: 33)
  • Exomes 𝑓: 0.20 (55 hom.)
• Consequence: SETX NM_015046.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.38

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=-0.89).
• BP6: Variant 9-132261977-T-C is Benign according to our data. Variant chr9-132261977-T-C is described in ClinVar as [Benign]. Clinvar id is 365305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.*2262A>G		3_prime_UTR_variant	26/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.*2262A>G		3_prime_UTR_variant	26/26	1	NM_015046.7	P1
SETX	ENST00000436441.5	c.*2262A>G		3_prime_UTR_variant	17/17	5
SETX	ENST00000477049.1	n.3446A>G		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0948 AC: 14417 AN: 152128 Hom.: 761 Cov.: 33

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0820

Gnomad OTH AF: 0.0965

GnomAD4 exome AF: 0.196 AC: 425 AN: 2168 Hom.: 55 Cov.: 0 AF XY: 0.181 AC XY: 196 AN XY: 1084

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.250

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0769

Gnomad4 OTH exome AF: 0.0904

GnomAD4 genome AF: 0.0948 AC: 14430 AN: 152246 Hom.: 763 Cov.: 33 AF XY: 0.0951 AC XY: 7080 AN XY: 74452

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.0703

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.0522

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0685

Gnomad4 NFE AF: 0.0820

Gnomad4 OTH AF: 0.0950

Alfa AF: 0.0888 Hom.: 529

Bravo AF: 0.0943

Asia WGS AF: 0.0960 AC: 334 AN: 3478

ClinVar

Significance: 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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 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	-0.89
CADD	Benign	0.15
DANN	Benign	0.44

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: rs997784; hg19: chr9-135137364;