rs29001665

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_015046.7(SETX):c.994C>T(p.Arg332Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.22

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 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

PP5

Variant 9-132331293-G-A is Pathogenic according to our data. Variant chr9-132331293-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132331293-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.994C>T	p.Arg332Trp	missense_variant	Exon 8 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.994C>T	p.Arg332Trp	missense_variant	Exon 8 of 26	1	NM_015046.7	ENSP00000224140.5		Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251404

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135878

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 12, 2021	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2016	The R332W variant in the SETX gene has been reported previously in the compound heterozygous state, opposite of a second frameshift variant, in 2 siblings with cerebellar atrophy, elevated AFP and late childhood/early adult onset ocular apraxia and sensory motor neuropathy (Moreira et al., 2004). Roda et al. (2014) reported a Columbian female with severe cerebellar atrophy, elevated AFP and young adult onset of progressive sensory motor neuropathy, ataxia, muscle weakness and ocular apraxia who harbored the R332W variant with a second frameshift variant, assumed on the opposite SETX allele. The R332W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R332W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E327V, I331K) have been reported in the Human Gene Mutation Database in association with SETX-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R332W as a pathogenic variant. -

SETX-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2024

The SETX c.994C>T variant is predicted to result in the amino acid substitution p.Arg332Trp. This variant has been reported in the compound heterozygous state in multiple individuals with ataxia-ocular apraxia (Table 1, Moreira et al. 2004. PubMed ID: 14770181; Figure 1, Roda et al. 2014. PubMed ID: 24814856). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. An in vitro experimental study using patient fibroblasts suggests this variant, in the compound heterozygous state, increases cells sensitivity to oxidative DNA damage (Figure 3, Roda et al. 2014. PubMed ID: 24814856). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.82

MutPred

0.76

Loss of disorder (P = 0.005);

MVP

0.84

MPC

0.079

ClinPred

0.84

GERP RS

6.2

Varity_R

0.18

gMVP

0.75

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