rs151117904

chr9-132264633-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015046.7(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 NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 0.238

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]

ACMG classification

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: {Likely_benign=6, Benign=3, Uncertain_significance=1}. 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 GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.7640T>C	p.Ile2547Thr	missense_variant	26/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.7640T>C	p.Ile2547Thr	missense_variant	26/26	1	NM_015046.7	P1
SETX	ENST00000436441.5	c.2453T>C	p.Ile818Thr	missense_variant	17/17	5
SETX	ENST00000477049.1	n.790T>C		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 652 AN: 152192 Hom.: 4 Cov.: 32

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.: 7 AF XY: 0.00386 AC XY: 524 AN XY: 135922

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.: 25 Cov.: 32 AF XY: 0.00512 AC XY: 3722 AN XY: 727248

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.: 4 Cov.: 32 AF XY: 0.00416 AC XY: 310 AN XY: 74480

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.: 4

Bravo AF: 0.00532

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00342 AC: 415

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00581

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 08, 2016	- -
Benign, no assertion criteria provided	literature only	Northcott Neuroscience Laboratory, ANZAC Research Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SETX: BP4, BS2 -
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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, Academic Medical Center	-	- -

not specified Benign:2

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

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

Invitae

Jan 29, 2024

- -

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. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 12, 2021

- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.70
Dann	Benign	0.39
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
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	T
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

Other links and lift over

dbSNP: rs151117904; hg19: chr9-135140020; COSMIC: COSV105039712;