9-132328523-TTCATCA-TTCATCATCA

Variant names:

• chr9-132328523-T-TTCA
• rs572772837
• NM_015046.7:c.3072_3074dupTGA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_015046.7(SETX):​c.3072_3074dupTGA​(p.Asp1024dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,952 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (9 hom.)
• Consequence: SETX NM_015046.7 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0500
• 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, 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_015046.7
• BP6: Variant 9-132328523-T-TTCA is Benign according to our data. Variant chr9-132328523-T-TTCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00197 (300/152292) while in subpopulation NFE AF = 0.00237 (161/68018). AF 95% confidence interval is 0.00207. There are 2 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.3072_3074dupTGA	p.Asp1024dup	disruptive_inframe_insertion	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.3072_3074dupTGA	p.Asp1024dup	disruptive_inframe_insertion	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.3072_3074dupTGA	p.Asp1024dup	disruptive_inframe_insertion	Exon 10 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.3072_3074dupTGA	p.Asp1024dup	disruptive_inframe_insertion	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.3072_3074dupTGA	p.Asp1024dup	disruptive_inframe_insertion	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.3072_3074dupTGA	p.Asp1024dup	disruptive_inframe_insertion	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152174 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00205 AC: 515 AN: 250820 AF XY: 0.00216

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00902

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00133 AC: 1943 AN: 1461660 Hom.: 9 Cov.: 36 AF XY: 0.00149 AC XY: 1086 AN XY: 727116

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.000671 AC: 30 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00108 AC: 93 AN: 86246

European-Finnish (FIN) AF: 0.00792 AC: 422 AN: 53258

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00118 AC: 1316 AN: 1111974

Other (OTH) AF: 0.00106 AC: 64 AN: 60390

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152292 Hom.: 2 Cov.: 33 AF XY: 0.00240 AC XY: 179 AN XY: 74466

African (AFR) AF: 0.000120 AC: 5 AN: 41564

American (AMR) AF: 0.00170 AC: 26 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00942 AC: 100 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00237 AC: 161 AN: 68018

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00255 Hom.: 0

Bravo AF: 0.00106

EpiCase AF: 0.00207

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	SETX-related disorder (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		0.050
Mutation Taster		=62/38	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs572772837; hg19: chr9-135203910; COSMIC: COSV56390694;