rs1056899

Variant names:

• chr9-132264514-T-C
• rs1056899
• NM_015046.7:c.7759A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-132264514-T-C
• chr9-132264514-T-A
• chr9-132264514-T-G

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.7759A>G​(p.Ile2587Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,704 control chromosomes in the GnomAD database, including 103,719 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 0.44 (18120 hom., cov: 31)
  • Exomes 𝑓: 0.32 (85599 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.19
• Publications: 45 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=1.2665112E-6).
• BP6: Variant 9-132264514-T-C is Benign according to our data. Variant chr9-132264514-T-C is described in ClinVar as Benign. ClinVar VariationId is 95669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 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.7759A>G	p.Ile2587Val	missense	Exon 26 of 26	NP_055861.3
	SETX	NM_001351528.2		c.7846A>G	p.Ile2616Val	missense	Exon 27 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.7759A>G	p.Ile2587Val	missense	Exon 26 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.7759A>G	p.Ile2587Val	missense	Exon 26 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.7885A>G	p.Ile2629Val	missense	Exon 28 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.7798A>G	p.Ile2600Val	missense	Exon 27 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67461 AN: 151896 Hom.: 18073 Cov.: 31

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.418

GnomAD2 exomes AF: 0.383 AC: 96108 AN: 251178 AF XY: 0.378

Gnomad AFR exome AF: 0.756

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.727

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.323 AC: 471972 AN: 1461690 Hom.: 85599 Cov.: 59 AF XY: 0.326 AC XY: 237034 AN XY: 727140

African (AFR) AF: 0.763 AC: 25538 AN: 33480

American (AMR) AF: 0.321 AC: 14354 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 10067 AN: 26136

East Asian (EAS) AF: 0.737 AC: 29275 AN: 39700

South Asian (SAS) AF: 0.438 AC: 37748 AN: 86258

European-Finnish (FIN) AF: 0.300 AC: 15982 AN: 53310

Middle Eastern (MID) AF: 0.507 AC: 2926 AN: 5768

European-Non Finnish (NFE) AF: 0.282 AC: 313628 AN: 1111932

Other (OTH) AF: 0.372 AC: 22454 AN: 60382

GnomAD4 genome AF: 0.444 AC: 67565 AN: 152014 Hom.: 18120 Cov.: 31 AF XY: 0.444 AC XY: 32992 AN XY: 74304

African (AFR) AF: 0.746 AC: 30931 AN: 41454

American (AMR) AF: 0.358 AC: 5462 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1371 AN: 3464

East Asian (EAS) AF: 0.714 AC: 3682 AN: 5160

South Asian (SAS) AF: 0.453 AC: 2184 AN: 4822

European-Finnish (FIN) AF: 0.293 AC: 3103 AN: 10576

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19637 AN: 67946

Other (OTH) AF: 0.416 AC: 880 AN: 2114

Alfa AF: 0.346 Hom.: 51594

Bravo AF: 0.465

TwinsUK AF: 0.274 AC: 1017

ALSPAC AF: 0.284 AC: 1095

ESP6500AA AF: 0.732 AC: 3227

ESP6500EA AF: 0.297 AC: 2550

ExAC AF: 0.392 AC: 47626

Asia WGS AF: 0.576 AC: 2005 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.307

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	2	not provided (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	0.068
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.0060
DANN	Benign	0.20
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0040
MPC		0.063
ClinPred		0.0010	T
GERP RS		-3.8
Varity_R		0.014
gMVP		0.072
Mutation Taster		=99/1	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: rs1056899; hg19: chr9-135139901; COSMIC: COSV56380941;