rs75682594

Variant names:

• chr9-132262539-C-A
• rs75682594
• NM_015046.7:c.*1700G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132262539-C-A
• chr9-132262539-C-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.*1700G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0469 in 152,500 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (534 hom., cov: 32)
  • Exomes 𝑓: 0.056 (1 hom.)
• Consequence: SETX NM_015046.7 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.328
• Publications: 2 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 (BayesDel_noAF=-0.82).
• BP6: Variant 9-132262539-C-A is Benign according to our data. Variant chr9-132262539-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 365311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 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.*1700G>T		3_prime_UTR	Exon 26 of 26	NP_055861.3
	SETX	NM_001351528.2		c.*1700G>T		3_prime_UTR	Exon 27 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.*1700G>T		3_prime_UTR	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.*1700G>T		3_prime_UTR	Exon 26 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.*1700G>T		3_prime_UTR	Exon 28 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.*1700G>T		3_prime_UTR	Exon 27 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7126 AN: 152058 Hom.: 533 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0602

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0507

GnomAD4 exome AF: 0.0556 AC: 18 AN: 324 Hom.: 1 Cov.: 0 AF XY: 0.0333 AC XY: 6 AN XY: 180

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0634 AC: 18 AN: 284

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.0469 AC: 7137 AN: 152176 Hom.: 534 Cov.: 32 AF XY: 0.0508 AC XY: 3780 AN XY: 74406

African (AFR) AF: 0.0231 AC: 959 AN: 41528

American (AMR) AF: 0.0610 AC: 932 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3470

East Asian (EAS) AF: 0.377 AC: 1942 AN: 5152

South Asian (SAS) AF: 0.124 AC: 599 AN: 4826

European-Finnish (FIN) AF: 0.0475 AC: 504 AN: 10604

Middle Eastern (MID) AF: 0.0931 AC: 27 AN: 290

European-Non Finnish (NFE) AF: 0.0272 AC: 1851 AN: 68006

Other (OTH) AF: 0.0545 AC: 115 AN: 2112

Alfa AF: 0.0291 Hom.: 14

Bravo AF: 0.0480

Asia WGS AF: 0.248 AC: 860 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	2	not provided (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.0
DANN	Benign	0.66
PhyloP100		0.33
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: rs75682594; hg19: chr9-135137926;