rs112089123

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015046.7(SETX):c.4660T>G(p.Cys1554Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,614,194 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts 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. C1554C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 58 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 2.92

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046750903).

BP6

Variant 9-132326938-A-C is Benign according to our data. Variant chr9-132326938-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 260505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132326938-A-C is described in Lovd as [Pathogenic]. Variant chr9-132326938-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00328 (500/152312) while in subpopulation SAS AF= 0.0242 (117/4826). AF 95% confidence interval is 0.0207. There are 0 homozygotes in gnomad4. There are 279 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7 linkuse as main transcript	c.4660T>G	p.Cys1554Gly	missense_variant	10/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6 linkuse as main transcript	c.4660T>G	p.Cys1554Gly	missense_variant	10/26	1	NM_015046.7	P1	Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.00329

AC:

500

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.0242

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00366

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00549

AC:

1379

AN:

251014

Hom.:

AF XY:

0.00639

AC XY:

867

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00272

Gnomad SAS exome

AF:

0.0235

Gnomad FIN exome

AF:

0.00753

Gnomad NFE exome

AF:

0.00352

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00464

AC:

6779

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

3807

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00484

Gnomad4 SAS exome

AF:

0.0207

Gnomad4 FIN exome

AF:

0.00700

Gnomad4 NFE exome

AF:

0.00363

Gnomad4 OTH exome

AF:

0.00545

GnomAD4 genome

AF:

0.00328

AC:

500

AN:

152312

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

279

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.0242

Gnomad4 FIN

AF:

0.00754

Gnomad4 NFE

AF:

0.00366

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00328

Hom.:

Bravo

AF:

0.00214

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00583

AC:

708

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00397

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SETX: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2018	This variant is associated with the following publications: (PMID: 28160950, 30054184, 30010942, 29605155, 21190393, 23129421) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Amyotrophic lateral sclerosis type 4

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

0.13

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0047

MetaSVM

Uncertain

0.77

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.031

Polyphen

1.0

Vest4

0.29

MVP

0.95

MPC

0.11

ClinPred

0.044

GERP RS

5.3

Varity_R

0.72

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over