rs29001584

Variant names:

• chr9-132330432-A-G
• rs29001584
• NM_015046.7:c.1166T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-132330432-A-G
• chr9-132330432-A-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_015046.7(SETX):​c.1166T>C​(p.Leu389Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001826566: Published functional studies demonstrate increased promoter methylation and decreased gene transcription, by reducing R-loops and BAMBI expression, while increasing TGF-B signaling (Grunseich et al., 2018).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L389F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 U:2
• Conservation: PhyloP100: 7.43
• Publications: 44 publications found

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: Orphanet, Ambry Genetics, 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001826566: Published functional studies demonstrate increased promoter methylation and decreased gene transcription, by reducing R-loops and BAMBI expression, while increasing TGF-B signaling (Grunseich et al., 2018).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132330431-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1685438.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 9-132330432-A-G is Pathogenic according to our data. Variant chr9-132330432-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015046.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	NM_015046.7	MANE Select	c.1166T>C	p.Leu389Ser	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.1166T>C	p.Leu389Ser	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.1166T>C	p.Leu389Ser	missense	Exon 10 of 26	NP_001338456.1	Q7Z333-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.1166T>C	p.Leu389Ser	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.1166T>C	p.Leu389Ser	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.1166T>C	p.Leu389Ser	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000106 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	Amyotrophic lateral sclerosis type 4 (2)
2	-	-	not provided (2)
-	1	-	Distal spinal muscular atrophy (1)
1	-	-	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (1)
1	-	-	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.0	L
PhyloP100		7.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.83		Gain of disorder (P = 0.0031)
MVP		0.97
MPC		0.50
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.95
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs29001584; hg19: chr9-135205819;