rs576141809

Variant names:

• chr9-132328430-CTTACTA-C
• rs576141809
• NM_015046.7:c.3162_3167delTAGTAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS1

The NM_015046.7(SETX):​c.3162_3167delTAGTAA​(p.Asn1054_Ser1055del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,840 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: SETX NM_015046.7 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0960
• 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 -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_015046.7.
• BP6: Variant 9-132328430-CTTACTA-C is Benign according to our data. Variant chr9-132328430-CTTACTA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 468498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000158 (24/152238) while in subpopulation EAS AF = 0.00366 (19/5194). AF 95% confidence interval is 0.00239. There are 1 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3162_3167delTAGTAA	p.Asn1054_Ser1055del	disruptive_inframe_deletion	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.3162_3167delTAGTAA	p.Asn1054_Ser1055del	disruptive_inframe_deletion	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.3162_3167delTAGTAA	p.Asn1054_Ser1055del	disruptive_inframe_deletion	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.3162_3167delTAGTAA	p.Asn1054_Ser1055del	disruptive_inframe_deletion	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.3162_3167delTAGTAA	p.Asn1054_Ser1055del	disruptive_inframe_deletion	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.3162_3167delTAGTAA	p.Asn1054_Ser1055del	disruptive_inframe_deletion	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000307 AC: 77 AN: 251064 AF XY: 0.000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00402

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461602 Hom.: 1 AF XY: 0.000117 AC XY: 85 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00302 AC: 120 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111948

Other (OTH) AF: 0.000513 AC: 31 AN: 60390

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000136

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Inborn genetic diseases (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		-0.096
Mutation Taster		=200/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs576141809; hg19: chr9-135203817;