rs1554820336

Variant names:

• chr9-132327212-T-C
• rs1554820336
• NM_015046.7:c.4386A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_015046.7(SETX):​c.4386A>G​(p.Glu1462Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.86
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-132327212-T-C is Benign according to our data. Variant chr9-132327212-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 536400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	NM_015046.7	MANE Select	c.4386A>G	p.Glu1462Glu	synonymous	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.4386A>G	p.Glu1462Glu	synonymous	Exon 10 of 27	NP_001338457.1
	SETX	NM_001351527.2		c.4386A>G	p.Glu1462Glu	synonymous	Exon 10 of 26	NP_001338456.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.4386A>G	p.Glu1462Glu	synonymous	Exon 10 of 26	ENSP00000224140.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Jul 11, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Benign:1

Nov 24, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Amyotrophic lateral sclerosis type 4 Benign:1

Feb 08, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 08, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.46
PhyloP100		-1.9

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: rs1554820336; hg19: chr9-135202599;