SETX p.Leu521Leu

Variant names:

• chr9-132330034-A-A
• NM_015046.7:c.

Your query was ambiguous. Multiple possible variants found:

• chr9-132330035--
• chr9-132330037-G-A
• chr9-132330035-C-A
• chr9-132330035-C-G
• chr9-132330035-C-T
• chr9-132330035-CAG-TAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015046.7(SETX):​c. variant causes a exon region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SETX NM_015046.7 exon_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.847
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.		exon_region	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.		exon_region	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.		exon_region	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.		exon_region	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.		exon_region	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.		exon_region	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-135205421;