rs201317659

Variant names:

• chr9-132300812-CAAG-C
• rs201317659
• NM_015046.7:c.5375-12_5375-10delCTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015046.7(SETX):​c.5375-12_5375-10delCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,610,992 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (6 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.10
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 9-132300812-CAAG-C is Benign according to our data. Variant chr9-132300812-CAAG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00543 (826/152082) while in subpopulation AFR AF = 0.0185 (766/41512). AF 95% confidence interval is 0.0174. There are 15 homozygotes in GnomAd4. There are 413 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

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.5375-12_5375-10delCTT		intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.5375-12_5375-10delCTT		intron	N/A	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.5375-12_5375-10delCTT		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.5375-12_5375-10delCTT		intron	N/A	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.5375-12_5375-10delCTT		intron	N/A	ENSP00000593275.1
	SETX	ENST00000923217.1		c.5375-12_5375-10delCTT		intron	N/A	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00541 AC: 822 AN: 151964 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00153 AC: 380 AN: 248510 AF XY: 0.00124

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000668 AC: 974 AN: 1458910 Hom.: 6 AF XY: 0.000606 AC XY: 440 AN XY: 725878

African (AFR) AF: 0.0178 AC: 594 AN: 33406

American (AMR) AF: 0.00161 AC: 72 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26090

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39558

South Asian (SAS) AF: 0.000268 AC: 23 AN: 85964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52402

Middle Eastern (MID) AF: 0.00177 AC: 10 AN: 5660

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1110978

Other (OTH) AF: 0.00164 AC: 99 AN: 60268

GnomAD4 genome AF: 0.00543 AC: 826 AN: 152082 Hom.: 15 Cov.: 32 AF XY: 0.00556 AC XY: 413 AN XY: 74330

African (AFR) AF: 0.0185 AC: 766 AN: 41512

American (AMR) AF: 0.00236 AC: 36 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67994

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00577

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	SETX-related disorder (1)
-	-	1	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (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		2.1
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201317659;

hg19: chr9-135176199;