rs145097270

chr9-132328369-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.3229G>A(p.Asp1077Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,032 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:8
• Conservation: PhyloP100: 4.08

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 (MetaRNN=0.013518751).
• BP6: Variant 9-132328369-C-T is Benign according to our data. Variant chr9-132328369-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 424687.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=7, Uncertain_significance=2}. Variant chr9-132328369-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00108 (164/152300) while in subpopulation AMR AF= 0.00359 (55/15302). AF 95% confidence interval is 0.00284. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.3229G>A	p.Asp1077Asn	missense_variant	10/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.3229G>A	p.Asp1077Asn	missense_variant	10/26	1	NM_015046.7	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00125 AC: 314 AN: 251092 Hom.: 3 AF XY: 0.00133 AC XY: 180 AN XY: 135710

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00116 AC: 1702 AN: 1461732 Hom.: 8 Cov.: 37 AF XY: 0.00119 AC XY: 864 AN XY: 727164

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00425

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74472

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00138 Hom.: 2

Bravo AF: 0.00112

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00110 AC: 133

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00218

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SETX: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 30, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2020	This variant is associated with the following publications: (PMID: 32253937, 18058631, 23129421, 23881933, 28832565, 32028661, 29525178, 27790088) -

Amyotrophic lateral sclerosis Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

UM ALS/MND Lab, University Of Malta

-

- -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Mar 07, 2017

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 30, 2020

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Amyotrophic lateral sclerosis type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2020

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.028	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.58	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.93	P
Vest4		0.12
MVP		0.81
MPC		0.11
ClinPred		0.16	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.24
gMVP		0.31

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: rs145097270; hg19: chr9-135203756; COSMIC: COSV56385421;