chr9-132264633-A-G

Position:

chr9-132264633-A-G

Variant summary

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

The ENST00000224140.6(SETX):c.7640T>C(p.Ile2547Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,614,206 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 25 hom. )

Consequence

SETX
ENST00000224140.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 0.238

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=0.0033735633).

BP6

Variant 9-132264633-A-G is Benign according to our data. Variant chr9-132264633-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 155748.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=6}. Variant chr9-132264633-A-G is described in Lovd as [Pathogenic]. Variant chr9-132264633-A-G is described in Lovd as [Likely_benign]. Variant chr9-132264633-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00428 (652/152312) while in subpopulation AMR AF= 0.0122 (186/15300). AF 95% confidence interval is 0.0107. There are 4 homozygotes in gnomad4. There are 310 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7 linkuse as main transcript	c.7640T>C	p.Ile2547Thr	missense_variant	26/26	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.7640T>C	p.Ile2547Thr	missense_variant	26/26	1	NM_015046.7	ENSP00000224140	P1	Q7Z333-1
SETX	ENST00000436441.5 linkuse as main transcript	c.2453T>C	p.Ile818Thr	missense_variant	17/17	5		ENSP00000409143
SETX	ENST00000477049.1 linkuse as main transcript	n.790T>C		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.00428

AC:

652

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00550

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.00391

AC:

983

AN:

251496

Hom.:

AF XY:

0.00386

AC XY:

524

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00572

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.00518

AC:

7573

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

3722

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.00691

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.000318

Gnomad4 NFE exome

AF:

0.00602

Gnomad4 OTH exome

AF:

0.00536

GnomAD4 genome

AF:

0.00428

AC:

652

AN:

152312

Hom.:

Cov.:

AF XY:

0.00416

AC XY:

310

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00550

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.00509

Hom.:

Bravo

AF:

0.00532

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00342

AC:

415

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00581

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SETX: BP4, BS2 -
Benign, no assertion criteria provided	literature only	Northcott Neuroscience Laboratory, ANZAC Research Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2020	This variant is associated with the following publications: (PMID: 25802885, 23129421, 22088787, 29080331, 21438761, 21190393, 27884173, 23447461, 25382069, 28430856) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 08, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Amyotrophic lateral sclerosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

UM ALS/MND Lab, University Of Malta

Sep 09, 2020

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 12, 2021

- -

Amyotrophic lateral sclerosis type 4

Benign:1

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. -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.70

DANN

Benign

0.39

DEOGEN2

Benign

0.093

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.32

T;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.0

.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.42

N;N

REVEL

Benign

0.11

Sift

Benign

0.32

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0

.;B

Vest4

0.044

MVP

0.43

MPC

0.093

ClinPred

0.00057

GERP RS

-3.4

Varity_R

0.017

gMVP

0.12

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