rs370363342

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_015046.7(SETX):c.1343A>G(p.Asp448Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,578,776 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.31

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052416384).

BP6

Variant 9-132330255-T-C is Benign according to our data. Variant chr9-132330255-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573505.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000854 (13/152242) while in subpopulation AMR AF= 0.00085 (13/15288). AF 95% confidence interval is 0.000503. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7 linkuse as main transcript	c.1343A>G	p.Asp448Gly	missense_variant	10/26	ENST00000224140.6	NP_055861.3	Q7Z333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6 linkuse as main transcript	c.1343A>G	p.Asp448Gly	missense_variant	10/26	1	NM_015046.7	ENSP00000224140.5		Q7Z333-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000146

AC:

AN:

226214

Hom.:

AF XY:

0.000115

AC XY:

AN XY:

121300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000992

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000186

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1426534

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

705352

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000828

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000509

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.15e-7

Gnomad4 OTH exome

AF:

0.0000511

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000382

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2020

The p.D448G variant (also known as c.1343A>G), located in coding exon 8 of the SETX gene, results from an A to G substitution at nucleotide position 1343. The aspartic acid at codon 448 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

- -

SETX-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2024

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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.31

Sift

Uncertain

0.014

Sift4G

Uncertain

0.032

Polyphen

0.15

Vest4

0.39

MVP

0.74

MPC

0.18

ClinPred

0.038

GERP RS

1.9

Varity_R

0.088

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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