rs3831154

Variant names:

• chr9-132298067-C-CA
• rs3831154
• NM_015046.7:c.5781+12dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_015046.7(SETX):​c.5781+12dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,582,696 control chromosomes in the GnomAD database, including 41,346 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6056 hom., cov: 26)
  • Exomes 𝑓: 0.19 (35290 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0720
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 9-132298067-C-CA is Benign according to our data. Variant chr9-132298067-C-CA is described in ClinVar as Benign. ClinVar VariationId is 95666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 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.5781+12dupT		intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.5781+12dupT		intron	N/A	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.5781+12dupT		intron	N/A	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.5781+12dupT		intron	N/A	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.5781+12dupT		intron	N/A	ENSP00000593275.1
	SETX	ENST00000923217.1		c.5781+12dupT		intron	N/A	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37990 AN: 151828 Hom.: 6044 Cov.: 26

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.248 AC: 62201 AN: 251208 AF XY: 0.247

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.689

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.192 AC: 274300 AN: 1430748 Hom.: 35290 Cov.: 28 AF XY: 0.196 AC XY: 140165 AN XY: 713828

African (AFR) AF: 0.392 AC: 12840 AN: 32758

American (AMR) AF: 0.193 AC: 8616 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6557 AN: 25926

East Asian (EAS) AF: 0.706 AC: 27875 AN: 39500

South Asian (SAS) AF: 0.361 AC: 30858 AN: 85566

European-Finnish (FIN) AF: 0.169 AC: 8991 AN: 53358

Middle Eastern (MID) AF: 0.328 AC: 1871 AN: 5702

European-Non Finnish (NFE) AF: 0.151 AC: 163160 AN: 1083990

Other (OTH) AF: 0.228 AC: 13532 AN: 59270

GnomAD4 genome AF: 0.250 AC: 38040 AN: 151948 Hom.: 6056 Cov.: 26 AF XY: 0.256 AC XY: 19006 AN XY: 74266

African (AFR) AF: 0.382 AC: 15799 AN: 41378

American (AMR) AF: 0.192 AC: 2925 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 919 AN: 3462

East Asian (EAS) AF: 0.670 AC: 3458 AN: 5158

South Asian (SAS) AF: 0.379 AC: 1825 AN: 4818

European-Finnish (FIN) AF: 0.169 AC: 1784 AN: 10560

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10630 AN: 67994

Other (OTH) AF: 0.230 AC: 485 AN: 2112

Alfa AF: 0.199 Hom.: 785

Bravo AF: 0.258

Asia WGS AF: 0.490 AC: 1704 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Amyotrophic Lateral Sclerosis, Dominant (1)
-	-	1	not provided (1)
-	-	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
PhyloP100		0.072
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: rs3831154; hg19: chr9-135173454;