rs151237267

Positions:

• chr9-132326843-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015046.7(SETX):​c.4755T>G​(p.Pro1585=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00719 in 1,614,212 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (72 hom.)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.09

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-132326843-A-C is Benign according to our data. Variant chr9-132326843-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 260506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132326843-A-C is described in Lovd as [Benign]. Variant chr9-132326843-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00517 (788/152328) while in subpopulation SAS AF= 0.0135 (65/4818). AF 95% confidence interval is 0.0109. There are 3 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.4755T>G	p.Pro1585=	synonymous_variant	10/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.4755T>G	p.Pro1585=	synonymous_variant	10/26	1	NM_015046.7	ENSP00000224140	P1

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 791 AN: 152210 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00695

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00610 AC: 1534 AN: 251378 Hom.: 6 AF XY: 0.00681 AC XY: 925 AN XY: 135850

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00690

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00740 AC: 10821 AN: 1461884 Hom.: 72 Cov.: 33 AF XY: 0.00770 AC XY: 5602 AN XY: 727242

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00766

Gnomad4 OTH exome AF: 0.00709

GnomAD4 genome AF: 0.00517 AC: 788 AN: 152328 Hom.: 3 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74500

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00694

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00713 Hom.: 5

Bravo AF: 0.00526

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00785

EpiControl AF: 0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SETX: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 28, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -

Amyotrophic lateral sclerosis type 4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs151237267; hg19: chr9-135202230; COSMIC: COSV99808531;