rs145438764

chr9-132342716-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_015046.7(SETX):c.472T>G(p.Leu158Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 1,613,718 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L158L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.75

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019678175).
• BP6: Variant 9-132342716-A-C is Benign according to our data. Variant chr9-132342716-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 365376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132342716-A-C is described in Lovd as [Likely_benign]. Variant chr9-132342716-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00347 (529/152276) while in subpopulation NFE AF= 0.00542 (369/68024). AF 95% confidence interval is 0.00497. There are 0 homozygotes in gnomad4. There are 276 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.472T>G	p.Leu158Val	missense_variant	5/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.472T>G	p.Leu158Val	missense_variant	5/26	1	NM_015046.7	P1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00542

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00375 AC: 943 AN: 251412 Hom.: 0 AF XY: 0.00396 AC XY: 538 AN XY: 135880

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00385

Gnomad FIN exome AF: 0.00426

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00488 AC: 7132 AN: 1461442 Hom.: 27 Cov.: 31 AF XY: 0.00497 AC XY: 3610 AN XY: 727072

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00408

Gnomad4 FIN exome AF: 0.00455

Gnomad4 NFE exome AF: 0.00552

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00371 AC XY: 276 AN XY: 74438

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00697

Gnomad4 NFE AF: 0.00542

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00517 Hom.: 1

Bravo AF: 0.00304

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00371 AC: 450

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SETX: BS1 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	This variant is associated with the following publications: (PMID: 25174650, 25382069, 27013921, 29525178) -

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

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. -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Feb 25, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 26, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 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 29, 2024

- -

Amyotrophic lateral sclerosis type 4 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 01, 2021

- -

SETX-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 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
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MVP		0.73
MPC		0.43
ClinPred		0.024	T
GERP RS		-0.026
Varity_R		0.34
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145438764; hg19: chr9-135218103;