9-132327165-G-T

Position:

chr9-132327165-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000224140.6(SETX):c.4433C>A(p.Ala1478Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,614,148 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1478T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

SETX
ENST00000224140.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 1.10

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04280147).

BP6

Variant 9-132327165-G-T is Benign according to our data. Variant chr9-132327165-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448329.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=8}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000368 (56/152288) while in subpopulation NFE AF= 0.00072 (49/68022). AF 95% confidence interval is 0.00056. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7 linkuse as main transcript	c.4433C>A	p.Ala1478Glu	missense_variant	10/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6 linkuse as main transcript	c.4433C>A	p.Ala1478Glu	missense_variant	10/26	1	NM_015046.7	ENSP00000224140	P1	Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000267

AC:

AN:

251380

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000501

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000562

AC:

822

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000580

AC XY:

422

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000692

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000368

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000628

Hom.:

Bravo

AF:

0.000385

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2024	Reported previously in an individual with corticobasal syndrome who had a loss of function variant in another gene associated with this disorder, and the authors concluded that the SETX variant was unlikely to be the cause the disorder (PMID: 35309588); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28642336, 32409511, 35309588, 23129421) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -

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

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.4433C>A (p.A1478E) alteration is located in exon 10 (coding exon 8) of the SETX gene. This alteration results from a C to A substitution at nucleotide position 4433, causing the alanine (A) at amino acid position 1478 to be replaced by a glutamic acid (E). Based on data from gnomAD, the A allele has an overall frequency of 0.028% (78/282780) total alleles studied. The highest observed frequency was 0.055% (4/7224) of Other alleles. This alteration was reported in a female with symmetrical lower limb amyotrophic paraparesis, onset in middle age. The alteration was absent in two healthy family members and was present in sample from her deceased father, who had generalized muscular atrophy; it was also present in one unrelated unaffected German control included in the study and in 2 control individuals in a different study of individuals with sporadic amyotrophic lateral sclerosis (Arning, 2013; Gibson, 2017). Additionally, this variant was reported in one Australian individual of German ancestry with clinical features suggesting amyotrophic lateral sclerosis (ALS); however, this variant has also been reported in one individual with corticobasal syndrome who has a variant in TBK1, a gene central to the development of ALS (McCann, 2020; Seibert, 2022). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2019

- -

Amyotrophic lateral sclerosis type 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

SETX-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2024

The SETX c.4433C>A variant is predicted to result in the amino acid substitution p.Ala1478Glu. This variant was reported in individuals with amyotrophic lateral sclerosis (Arning et al. 2013. PubMed ID: 23129421; McCann et al. 2020. PubMed ID: 32409511) as well as in unaffected controls (Arning et al. 2013. PubMed ID: 23129421). This variant is reported in 0.052% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.27

CADD

Benign

8.8

DANN

Benign

0.89

DEOGEN2

Benign

0.20

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.36

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.92

REVEL

Benign

0.21

Sift

Uncertain

0.0030

Sift4G

Benign

0.085

Polyphen

0.10

Vest4

0.29

MVP

0.80

MPC

0.11

ClinPred

0.036

GERP RS

1.9

Varity_R

0.11

gMVP

0.11

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