Genetic Variant SETX:p.Ser761Trp (chr9-132329316-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_015046.7(SETX):c.2282C>G(p.Ser761Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.49

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7 link	c.2282C>G	p.Ser761Trp	missense_variant	Exon 10 of 26	ENST00000224140.6	NP_055861.3	Q7Z333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6 link	c.2282C>G	p.Ser761Trp	missense_variant	Exon 10 of 26	1	NM_015046.7	ENSP00000224140.5		Q7Z333-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250894

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461512

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

SETX-related disorder

Uncertain:1

May 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SETX c.2282C>G variant is predicted to result in the amino acid substitution p.Ser761Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-135204703-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Benign

0.18

Eigen_PC

Benign

0.082

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.065

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.050

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.51

MutPred

0.20

Loss of phosphorylation at S761 (P = 0.0143);

MVP

0.85

MPC

0.49

ClinPred

0.78

GERP RS

4.7

Varity_R

0.11

gMVP

0.36

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