rs372193033

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP6

The NM_015046.7(SETX):​c.968G>A​(p.Ser323Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000222 in 1,613,980 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S323G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

4
6
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 6.30
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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.759
BP6
Variant 9-132331319-C-T is Benign according to our data. Variant chr9-132331319-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536383.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SETXNM_015046.7 linkc.968G>A p.Ser323Asn 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
SETXENST00000224140.6 linkc.968G>A p.Ser323Asn missense_variant Exon 8 of 26 1 NM_015046.7 ENSP00000224140.5 Q7Z333-1

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000219
AC:
55
AN:
251440
AF XY:
0.000243
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.000185
Gnomad NFE exome
AF:
0.000404
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000227
AC:
332
AN:
1461836
Hom.:
0
Cov.:
32
AF XY:
0.000209
AC XY:
152
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
AC:
1
AN:
33478
Gnomad4 AMR exome
AF:
0.0000224
AC:
1
AN:
44724
Gnomad4 ASJ exome
AF:
0.000230
AC:
6
AN:
26132
Gnomad4 EAS exome
AF:
0.0000252
AC:
1
AN:
39692
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86254
Gnomad4 FIN exome
AF:
0.000150
AC:
8
AN:
53416
Gnomad4 NFE exome
AF:
0.000280
AC:
311
AN:
1111980
Gnomad4 Remaining exome
AF:
0.0000662
AC:
4
AN:
60392
Heterozygous variant carriers
0
18
35
53
70
88
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0000241
AC:
0.0000241289
AN:
0.0000241289
Gnomad4 AMR
AF:
0.00
AC:
0
AN:
0
Gnomad4 ASJ
AF:
0.000576
AC:
0.000576369
AN:
0.000576369
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.000189
AC:
0.000188679
AN:
0.000188679
Gnomad4 NFE
AF:
0.000309
AC:
0.000308733
AN:
0.000308733
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000381
Hom.:
0
Bravo
AF:
0.000128
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000239
AC:
29
EpiCase
AF:
0.000327
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Nov 02, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Previously reported in an individual with apparently sporadic ALS, who also harbored a variant in a different gene associated with ALS (PMID: 25382069); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25869998, 29605155, 25382069) -

May 07, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

BP4, PM2_moderate -

Sep 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

SETX: PM2 -

Inborn genetic diseases Uncertain:1
Dec 02, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Unlikely to be causative of SETX-related juvenile amyotrophic lateral sclerosis (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SETX-related disorder Uncertain:1
Sep 21, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The SETX c.968G>A variant is predicted to result in the amino acid substitution p.Ser323Asn. This variant was reported in two individuals with amyotrophic lateral sclerosis, with one individual also harboring a missense variant in DCTN1 (Cady et al. 2015. PubMed ID: 25382069, Table 2 and Table 4). This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain significance (http://www.ncbi.nlm.nih.gov/clinvar/variation/536383/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1
Feb 24, 2021
Athena Diagnostics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Benign:1
Jun 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
D
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.76
D
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
1.0
L
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.23
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.88
MVP
0.77
MPC
0.42
ClinPred
0.22
T
GERP RS
6.2
Varity_R
0.35
gMVP
0.73
Mutation Taster
=2/98
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs372193033; hg19: chr9-135206706; COSMIC: COSV104552887; API