rs374656811

Positions:

• chr9-132296882-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015046.7(SETX):​c.5949+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00122 in 1,613,814 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: SETX NM_015046.7 splice_region, intron
• Scores: Splicing: ADA: 0.8761
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: 4.85

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-132296882-C-T is Benign according to our data. Variant chr9-132296882-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 488730.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}. Variant chr9-132296882-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000756 (115/152130) while in subpopulation NFE AF= 0.00134 (91/68022). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.5949+5G>A		splice_region_variant, intron_variant		ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.5949+5G>A		splice_region_variant, intron_variant		1	NM_015046.7	ENSP00000224140.5
SETX	ENST00000436441.5	c.675+5G>A		splice_region_variant, intron_variant		5		ENSP00000409143.1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000748 AC: 188 AN: 251436 Hom.: 0 AF XY: 0.000714 AC XY: 97 AN XY: 135892

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00127 AC: 1857 AN: 1461684 Hom.: 4 Cov.: 31 AF XY: 0.00120 AC XY: 876 AN XY: 727156

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00154

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000756 AC: 115 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.000700 AC XY: 52 AN XY: 74324

Gnomad4 AFR AF: 0.000242

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000620

EpiCase AF: 0.000600

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 30, 2024	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2024	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on splicing -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	The SETX c.5949+5G>A variant (rs374656811), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 488730). This variant is found in the non-Finnish European population with an overall allele frequency of 0.13% (174/129164 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, although RNA studies would be required to confirm this. Given the lack of clinical and functional data, the significance of the c.5949+5G>A variant is uncertain at this time. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2022

The c.5949+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 12 in the SETX gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this variant is unlikely to be causative of juvenile amyotrophic lateral sclerosis 4 (ALS4); however, its contribution to the development of spinocerebellar ataxia with axonal neuropathy 2 (SCAN2) is uncertain. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change falls in intron 14 of the SETX gene. It does not directly change the encoded amino acid sequence of the SETX protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374656811, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SETX-related conditions. ClinVar contains an entry for this variant (Variation ID: 488730). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 17, 2017

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 24, 2020

- -

Amyotrophic lateral sclerosis type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SETX-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Uncertain	25
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs374656811; hg19: chr9-135172269;