NM_015046.7:c.3663G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015046.7(SETX):​c.3663G>T​(p.Lys1221Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0120

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • amyotrophic lateral sclerosis type 4
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
  • distal hereditary motor neuropathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25920248).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SETXNM_015046.7 linkc.3663G>T p.Lys1221Asn missense_variant Exon 10 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.3663G>T p.Lys1221Asn missense_variant Exon 10 of 26 1 NM_015046.7 ENSP00000224140.5 Q7Z333-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461806
Hom.:
0
Cov.:
67
AF XY:
0.00000138
AC XY:
1
AN XY:
727206
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33464
American (AMR)
AF:
0.00
AC:
0
AN:
44700
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86246
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111992
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.39
N
LIST_S2
Benign
0.72
T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.26
T
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Uncertain
2.4
M
PhyloP100
-0.012
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.88
N
REVEL
Benign
0.24
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.054
T
Polyphen
0.99
D
Vest4
0.18
MutPred
0.18
Gain of sheet (P = 0.0036);
MVP
0.77
MPC
0.26
ClinPred
0.75
D
GERP RS
2.7
Varity_R
0.14
gMVP
0.24
Mutation Taster
=91/9
polymorphism

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

Other links and lift over

dbSNP: rs12344006; hg19: chr9-135203322; COSMIC: COSV56379347; API