rs73659013

chr9-132342670-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.498+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,495,156 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (39 hom., cov: 32)
  • Exomes 𝑓: 0.019 (322 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.936

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=-0.93).
• BP6: Variant 9-132342670-C-T is Benign according to our data. Variant chr9-132342670-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132342670-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0215 (3275/152264) while in subpopulation SAS AF= 0.04 (193/4824). AF 95% confidence interval is 0.0354. There are 39 homozygotes in gnomad4. There are 1685 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.498+20G>A		intron_variant		ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.498+20G>A		intron_variant		1	NM_015046.7	P1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3274 AN: 152146 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00924

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.00980

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0212 AC: 5336 AN: 251200 Hom.: 82 AF XY: 0.0221 AC XY: 2998 AN XY: 135772

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.00674

Gnomad ASJ exome AF: 0.0360

Gnomad EAS exome AF: 0.0103

Gnomad SAS exome AF: 0.0416

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0193 AC: 25926 AN: 1342892 Hom.: 322 Cov.: 20 AF XY: 0.0200 AC XY: 13526 AN XY: 675140

Gnomad4 AFR exome AF: 0.0260

Gnomad4 AMR exome AF: 0.00682

Gnomad4 ASJ exome AF: 0.0347

Gnomad4 EAS exome AF: 0.0121

Gnomad4 SAS exome AF: 0.0392

Gnomad4 FIN exome AF: 0.0310

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0215 AC: 3275 AN: 152264 Hom.: 39 Cov.: 32 AF XY: 0.0226 AC XY: 1685 AN XY: 74460

Gnomad4 AFR AF: 0.0256

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.0400

Gnomad4 FIN AF: 0.0340

Gnomad4 NFE AF: 0.0189

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0219 Hom.: 7

Bravo AF: 0.0186

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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

not provided Benign:2

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

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

- -

Amyotrophic lateral sclerosis type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.50
Dann	Benign	0.42

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: rs73659013; hg19: chr9-135218057; COSMIC: COSV56381102;