rs534723946

Positions:

Variant summary

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

The NM_015046.7(SETX):c.1504C>T(p.Arg502Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,614,192 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. R502Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00029 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 3 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:2

Conservation

PhyloP100: 1.97

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=0.012727529).

BP6

Variant 9-132330094-G-A is Benign according to our data. Variant chr9-132330094-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 155742.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=1, Benign=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000289 (44/152344) while in subpopulation SAS AF= 0.00621 (30/4830). AF 95% confidence interval is 0.00447. There are 1 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7 linkuse as main transcript	c.1504C>T	p.Arg502Trp	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.1504C>T	p.Arg502Trp	missense_variant	10/26	1	NM_015046.7	P1	Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000541

AC:

136

AN:

251320

Hom.:

AF XY:

0.000648

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.00353

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000254

AC:

372

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

237

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00306

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000683

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000289

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000880

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SETX p.Arg502Trp variant was identified in 2 of 310 proband chromosomes (frequency: 0.0065) from individuals with inherited peripheral neuropathies or amyotrophic lateral sclerosis (Drew_2015_PMID:25802885; Liu_2019_PMID:31788332). The variant was identified in dbSNP (ID: rs534723946) and ClinVar (classified as uncertain significance by the Inherited Neuropathy Consortium and Genomic Research Center, Shahid Beheshti University of Medical Sciences, and as probable-pathogenic by the Northcott Neuroscience Laboratory, ANZAC Research Institute). The variant was identified in control databases in 138 of 282726 chromosomes at a frequency of 0.0004881 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 108 of 30616 chromosomes (freq: 0.003528), Other in 5 of 7218 chromosomes (freq: 0.000693), East Asian in 12 of 19954 chromosomes (freq: 0.000601), African in 2 of 24966 chromosomes (freq: 0.00008), European (non-Finnish) in 9 of 129050 chromosomes (freq: 0.00007) and Latino in 2 of 35438 chromosomes (freq: 0.000056), but was not observed in the Ashkenazi Jewish, or European (Finnish) populations. The p.Arg502 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely pathogenic, no assertion criteria provided	literature only	Northcott Neuroscience Laboratory, ANZAC Research Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2019	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 17, 2020	- -

Amyotrophic lateral sclerosis type 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The amino acid Arg at position 502 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Likely_pathogenic, however details are not available for independent assessment. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg502Trp in SETX is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Apr 27, 2019

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.80

D;D;D

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.61

MutPred

0.43

Loss of disorder (P = 0.0273);

MVP

0.86

MPC

0.44

ClinPred

0.79

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.25

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