rs587776537

Positions:

• chr9-132346303-CAAG-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. 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 (★).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• 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 id is 2297.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132346303-CAAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.343_345delCTT	p.Leu115del	conservative_inframe_deletion	4/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.343_345delCTT	p.Leu115del	conservative_inframe_deletion	4/26	1	NM_015046.7	ENSP00000224140.5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2022

The c.343_345delCTT variant (also known as p.L115del) is located in coding exon 2 of the SETX gene. This variant results from an in-frame CTT deletion at nucleotide positions 343 to 345. This results in the in-frame deletion of a leucine at codon 115. This alteration was reported as homozygous in two siblings diagnosed with ataxia and sensory neuropathy. Additional features include mild cognitive impairment, distal muscular atrophy, areflexia, nystagmus, myotonic phenomenon at the hands, impairment of vibration and position sense, and resting tremor of the head and upper left limb (Airoldi G et al. Neurogenetics, 2010 Feb;11:91-100). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this variant is expected to be causative of autosomal recessive spinocerebellar ataxia with axonal neuropathy 2 (SCAN2) when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant juvenile amyotrophic lateral sclerosis 4 (ALS4) is unclear. -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs587776537; hg19: chr9-135221690;