rs587776537

Variant names:

• chr9-132346303-CAAG-C
• rs587776537
• NM_015046.7:c.343_345delCTT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PM4_Supporting PP5_Moderate

The NM_015046.7(SETX):​c.343_345delCTT​(p.Leu115del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000742304: Functional analysis demonstrated that the lymphoblastoid cell lines derived from an affected patient showed sensitivity to DNA-damaging agents. SKNBE cells were transfected with constructs expressing this alteration and showed increased cell death (Airoldi G et al. Neurogenetics, 2010 Feb" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SETX NM_015046.7 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.98
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000742304: Functional analysis demonstrated that the lymphoblastoid cell lines derived from an affected patient showed sensitivity to DNA-damaging agents. SKNBE cells were transfected with constructs expressing this alteration and showed increased cell death (Airoldi G et al. Neurogenetics, 2010 Feb;11:91-100).
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_015046.7. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-132346303-CAAG-C is Pathogenic according to our data. Variant chr9-132346303-CAAG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2297.Status of the report is criteria_provided_single_submitter, 1 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.343_345delCTT	p.Leu115del	conservative_inframe_deletion	Exon 4 of 26	NP_055861.3
	SETX	NM_001351528.2		c.343_345delCTT	p.Leu115del	conservative_inframe_deletion	Exon 4 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.343_345delCTT	p.Leu115del	conservative_inframe_deletion	Exon 4 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.343_345delCTT	p.Leu115del	conservative_inframe_deletion	Exon 4 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.343_345delCTT	p.Leu115del	conservative_inframe_deletion	Exon 4 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.343_345delCTT	p.Leu115del	conservative_inframe_deletion	Exon 4 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1461756 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=42/58	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: rs587776537; hg19: chr9-135221690;