9-132295858-C-T

Variant names:

• chr9-132295858-C-T
• rs73661157
• NM_015046.7:c.6106+14G>A

Variant summary

Our verdict is Benign. The variant received -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:13
• Conservation: PhyloP100: -1.70
• Publications: 3 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=-0.79).
• BP6: Variant 9-132295858-C-T is Benign according to our data. Variant chr9-132295858-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015046.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	NM_015046.7	MANE Select	c.6106+14G>A		intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.6106+14G>A		intron	N/A	NP_001338457.1
	SETX	NM_001351527.2		c.6106+14G>A		intron	N/A	NP_001338456.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.6106+14G>A		intron	N/A	ENSP00000224140.5
	SETX	ENST00000436441.5	TSL:5	c.832+14G>A		intron	N/A	ENSP00000409143.1

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

GnomAD2 exomes AF: 0.0149 AC: 3655 AN: 245130 AF XY: 0.0149

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 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

African (AFR) AF: 0.0253 AC: 845 AN: 33392

American (AMR) AF: 0.00626 AC: 277 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.0341 AC: 885 AN: 25964

East Asian (EAS) AF: 0.000656 AC: 26 AN: 39634

South Asian (SAS) AF: 0.0182 AC: 1560 AN: 85846

European-Finnish (FIN) AF: 0.0239 AC: 1273 AN: 53216

Middle Eastern (MID) AF: 0.0194 AC: 111 AN: 5732

European-Non Finnish (NFE) AF: 0.0134 AC: 14866 AN: 1109224

Other (OTH) AF: 0.0149 AC: 899 AN: 60228

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

African (AFR) AF: 0.0250 AC: 1040 AN: 41568

American (AMR) AF: 0.00830 AC: 127 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 114 AN: 3466

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.0157 AC: 76 AN: 4830

European-Finnish (FIN) AF: 0.0266 AC: 282 AN: 10606

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0153 AC: 1040 AN: 68026

Other (OTH) AF: 0.0156 AC: 33 AN: 2112

Alfa AF: 0.0127 Hom.: 5

Bravo AF: 0.0163

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

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

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Aug 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

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;C1865409:Amyotrophic lateral sclerosis type 4 Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.22
DANN	Benign	0.59
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73661157; hg19: chr9-135171245;