rs882709

Variant names:

• chr9-132329619-G-C
• rs882709
• NM_015046.7:c.1979C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-132329619-G-C
• chr9-132329619-G-T

Variant summary

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

The NM_001351528.2(SETX):​c.1979C>G​(p.Ala660Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0848 in 1,613,224 control chromosomes in the GnomAD database, including 10,094 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A660V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1853 hom., cov: 33)
  • Exomes 𝑓: 0.081 (8241 hom.)
• Consequence: SETX NM_001351528.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.27
• Publications: 37 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: Ambry Genetics, Orphanet, 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=3.9163232E-4).
• BP6: Variant 9-132329619-G-C is Benign according to our data. Variant chr9-132329619-G-C is described in ClinVar as Benign. ClinVar VariationId is 95659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351528.2. 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.1979C>G	p.Ala660Gly	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.1979C>G	p.Ala660Gly	missense	Exon 10 of 27	NP_001338457.1
	SETX	NM_001351527.2		c.1979C>G	p.Ala660Gly	missense	Exon 10 of 26	NP_001338456.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.1979C>G	p.Ala660Gly	missense	Exon 10 of 26	ENSP00000224140.5
	SETX	ENST00000923216.1		c.1979C>G	p.Ala660Gly	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.1979C>G	p.Ala660Gly	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19006 AN: 152050 Hom.: 1853 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0866

Gnomad ASJ AF: 0.0936

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0591

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.117 AC: 29433 AN: 250562 AF XY: 0.114

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.0951

Gnomad ASJ exome AF: 0.0869

Gnomad EAS exome AF: 0.448

Gnomad FIN exome AF: 0.0682

Gnomad NFE exome AF: 0.0609

Gnomad OTH exome AF: 0.0921

GnomAD4 exome AF: 0.0806 AC: 117728 AN: 1461056 Hom.: 8241 Cov.: 36 AF XY: 0.0816 AC XY: 59300 AN XY: 726822

African (AFR) AF: 0.236 AC: 7905 AN: 33426

American (AMR) AF: 0.0930 AC: 4155 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0897 AC: 2343 AN: 26120

East Asian (EAS) AF: 0.418 AC: 16599 AN: 39676

South Asian (SAS) AF: 0.142 AC: 12253 AN: 86182

European-Finnish (FIN) AF: 0.0667 AC: 3549 AN: 53216

Middle Eastern (MID) AF: 0.123 AC: 709 AN: 5766

European-Non Finnish (NFE) AF: 0.0575 AC: 63943 AN: 1111616

Other (OTH) AF: 0.104 AC: 6272 AN: 60360

GnomAD4 genome AF: 0.125 AC: 19025 AN: 152168 Hom.: 1853 Cov.: 33 AF XY: 0.127 AC XY: 9435 AN XY: 74392

African (AFR) AF: 0.228 AC: 9462 AN: 41514

American (AMR) AF: 0.0867 AC: 1325 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0936 AC: 325 AN: 3472

East Asian (EAS) AF: 0.422 AC: 2185 AN: 5176

South Asian (SAS) AF: 0.162 AC: 779 AN: 4820

European-Finnish (FIN) AF: 0.0596 AC: 632 AN: 10596

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0591 AC: 4017 AN: 67992

Other (OTH) AF: 0.104 AC: 219 AN: 2104

Alfa AF: 0.0779 Hom.: 222

Bravo AF: 0.134

TwinsUK AF: 0.0572 AC: 212

ALSPAC AF: 0.0579 AC: 223

ESP6500AA AF: 0.223 AC: 982

ESP6500EA AF: 0.0579 AC: 498

ExAC AF: 0.121 AC: 14697

Asia WGS AF: 0.281 AC: 978 AN: 3478

EpiCase AF: 0.0599

EpiControl AF: 0.0621

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	0.099
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.00039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.17	T
Polyphen		0.42	B
Vest4		0.055
MPC		0.13
ClinPred		0.0020	T
GERP RS		2.1
Varity_R		0.048
gMVP		0.13
Mutation Taster		=97/3	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: rs882709; hg19: chr9-135205006; COSMIC: COSV56380223;