rs1185193

Variant names:

• chr9-132328022-A-C
• rs1185193
• NM_015046.7:c.3576T>G

Your query was ambiguous. Multiple possible variants found:

• chr9-132328022-A-C
• chr9-132328022-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015046.7(SETX):​c.3576T>G​(p.Asp1192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 1,613,658 control chromosomes in the GnomAD database, including 550,679 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (46132 hom., cov: 31)
  • Exomes 𝑓: 0.82 (504547 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.15
• Publications: 53 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• distal hereditary motor neuropathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.1617526E-7).
• BP6: Variant 9-132328022-A-C is Benign according to our data. Variant chr9-132328022-A-C is described in ClinVar as Benign. ClinVar VariationId is 95661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015046.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	NM_015046.7	MANE Select	c.3576T>G	p.Asp1192Glu	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.3576T>G	p.Asp1192Glu	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.3576T>G	p.Asp1192Glu	missense	Exon 10 of 26	NP_001338456.1	Q7Z333-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.3576T>G	p.Asp1192Glu	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.3576T>G	p.Asp1192Glu	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.3576T>G	p.Asp1192Glu	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116730 AN: 151978 Hom.: 46110 Cov.: 31

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.875

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.858

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.788

GnomAD2 exomes AF: 0.768 AC: 192797 AN: 251086 AF XY: 0.768

Gnomad AFR exome AF: 0.642

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.783

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.857

Gnomad NFE exome AF: 0.857

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.823 AC: 1203440 AN: 1461562 Hom.: 504547 Cov.: 58 AF XY: 0.819 AC XY: 595396 AN XY: 727076

African (AFR) AF: 0.631 AC: 21112 AN: 33452

American (AMR) AF: 0.813 AC: 36323 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 20410 AN: 26132

East Asian (EAS) AF: 0.295 AC: 11698 AN: 39696

South Asian (SAS) AF: 0.656 AC: 56555 AN: 86154

European-Finnish (FIN) AF: 0.856 AC: 45699 AN: 53412

Middle Eastern (MID) AF: 0.691 AC: 3984 AN: 5764

European-Non Finnish (NFE) AF: 0.864 AC: 960126 AN: 1111888

Other (OTH) AF: 0.787 AC: 47533 AN: 60378

GnomAD4 genome AF: 0.768 AC: 116803 AN: 152096 Hom.: 46132 Cov.: 31 AF XY: 0.763 AC XY: 56734 AN XY: 74372

African (AFR) AF: 0.643 AC: 26622 AN: 41426

American (AMR) AF: 0.817 AC: 12488 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2664 AN: 3470

East Asian (EAS) AF: 0.331 AC: 1712 AN: 5172

South Asian (SAS) AF: 0.636 AC: 3067 AN: 4820

European-Finnish (FIN) AF: 0.858 AC: 9082 AN: 10584

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.860 AC: 58496 AN: 68016

Other (OTH) AF: 0.786 AC: 1660 AN: 2112

Alfa AF: 0.816 Hom.: 170218

Bravo AF: 0.758

TwinsUK AF: 0.866 AC: 3211

ALSPAC AF: 0.856 AC: 3299

ESP6500AA AF: 0.659 AC: 2902

ESP6500EA AF: 0.862 AC: 7411

ExAC AF: 0.763 AC: 92682

Asia WGS AF: 0.516 AC: 1796 AN: 3478

EpiCase AF: 0.856

EpiControl AF: 0.849

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	1	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.0010
DANN	Benign	0.74
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	L
PhyloP100		-1.2
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.27
Sift	Benign	0.38	T
Sift4G	Benign	0.46	T
Polyphen		0.0010	B
Vest4		0.010
MutPred		0.049		Gain of methylation at K1190 (P = 0.0802)
MPC		0.070
ClinPred		0.020	T
GERP RS		-9.5
Varity_R		0.071
gMVP		0.060
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1185193; hg19: chr9-135203409; COSMIC: COSV56383702;