9-132295858-C-T

Position:

• chr9-132295858-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015046.7(SETX):​c.6106+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,609,814 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (31 hom., cov: 33)
  • Exomes 𝑓: 0.014 (175 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.70

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=-0.79).
• BP6: Variant 9-132295858-C-T is Benign according to our data. Variant chr9-132295858-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132295858-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.018 (2743/152306) while in subpopulation AFR AF= 0.025 (1040/41568). AF 95% confidence interval is 0.0238. There are 31 homozygotes in gnomad4. There are 1384 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.6106+14G>A		intron_variant		ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.6106+14G>A		intron_variant		1	NM_015046.7	P1
SETX	ENST00000436441.5	c.832+14G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2742 AN: 152188 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0149 AC: 3655 AN: 245130 Hom.: 41 AF XY: 0.0149 AC XY: 1972 AN XY: 132584

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00597

Gnomad ASJ exome AF: 0.0351

Gnomad EAS exome AF: 0.00161

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0142 AC: 20742 AN: 1457508 Hom.: 175 Cov.: 31 AF XY: 0.0143 AC XY: 10390 AN XY: 724852

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.00626

Gnomad4 ASJ exome AF: 0.0341

Gnomad4 EAS exome AF: 0.000656

Gnomad4 SAS exome AF: 0.0182

Gnomad4 FIN exome AF: 0.0239

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0180 AC: 2743 AN: 152306 Hom.: 31 Cov.: 33 AF XY: 0.0186 AC XY: 1384 AN XY: 74470

Gnomad4 AFR AF: 0.0250

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.0266

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0115 Hom.: 4

Bravo AF: 0.0163

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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. -

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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.22
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73661157; hg19: chr9-135171245;