chr9-132311819-TTCTC-T

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]

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
SETXNM_015046.7 linkc.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
SETXENST00000224140.6 linkc.5308_5311delGAGA p.Glu1770IlefsTer15 frameshift_variant Exon 11 of 26 1 NM_015046.7 ENSP00000224140.5 Q7Z333-1
SETXENST00000436441.5 linkc.34_37delGAGA p.Glu12IlefsTer15 frameshift_variant Exon 1 of 17 5 ENSP00000409143.1 X6RI79

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152210
Hom.:
0
Cov.:
32
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:
6
AN:
251016
Hom.:
0
AF XY:
0.0000295
AC XY:
4
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:
41
AN:
1461450
Hom.:
0
AF XY:
0.0000316
AC XY:
23
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:
4
AN:
152328
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
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

- -

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. -

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) -

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

- -

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 -

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. -

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.

Other links and lift over

dbSNP: rs750959420; hg19: chr9-135187206; API