Genetic Variant SETX:p.Glu1770IlefsTer15 (chr9-132311819-TTCTC-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_015046.7(SETX):c.5308_5311delGAGA(p.Glu1770IlefsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

SETX
NM_015046.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.67

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 9-132311819-TTCTC-T is Pathogenic according to our data. Variant chr9-132311819-TTCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132311819-TTCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.5308_5311delGAGA	p.Glu1770IlefsTer15	frameshift_variant	Exon 11 of 26	ENST00000224140.6	NP_055861.3	Q7Z333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6 link	c.5308_5311delGAGA	p.Glu1770IlefsTer15	frameshift_variant	Exon 11 of 26	1	NM_015046.7	ENSP00000224140.5		Q7Z333-1
SETX	ENST00000436441.5 link	c.34_37delGAGA	p.Glu12IlefsTer15	frameshift_variant	Exon 1 of 17	5		ENSP00000409143.1		X6RI79

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251016

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1461450

Hom.:

AF XY:

0.0000316

AC XY:

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Mar 14, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 31656689, 31493945, 18405395, 33624863, 29858556, 19696032, 30560021, 27528516) -

Jul 28, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to be associated with disease in at least one family. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Pathogenic:2

Feb 08, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2018

Institute of Human Genetics, Cologne University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Abnormal central motor function

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu1770Ilefs*15) in the SETX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETX are known to be pathogenic (PMID: 14770181). This variant is present in population databases (rs750959420, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with autosomal recessive cerebellar ataxia (PMID: 18405395). ClinVar contains an entry for this variant (Variation ID: 448333). For these reasons, this variant has been classified as Pathogenic. -

Amyotrophic lateral sclerosis

Pathogenic:1

Jul 31, 2020

UM ALS/MND Lab, University Of Malta

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

Allele frequency for the Glu1770Ilefs*15 variant in SETX was 0.000075 in ALS cases and 0 in controls within the Project MinE ALS case-control cohort, which favors evidence supporting our criteria to be classified as likely pathogenic -

SETX-related disorder

Pathogenic:1

Mar 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SETX c.5308_5311delGAGA variant is predicted to result in a frameshift and premature protein termination (p.Glu1770Ilefs*15). This variant was reported in the homozygous state in multiple individuals with autosomal recessive spinocerebellar ataxia and was found to segregate with disorder in at least two unrelated families (Nicolaou et al. 2008. PubMed ID: 18405395; Algahtani et al. 2018. PubMed ID: 30560021; Table S1, Vural et al. 2021. PubMed ID: 33624863). This variant was also documented along with a canonical splice variant in an individual with autosomal recessive spinocerebellar ataxia (Marelliet al. 2016. PubMed ID: 27528516). None of the heterozygous carriers of this variant were reported to be symptomatic. This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in SETX are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cerebellar ataxia

Pathogenic:1

Aug 06, 2018

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over