9-132269711-TAA-TAAA

Variant names:

• chr9-132269711-T-TA
• rs531485265
• NM_015046.7:c.7200-10dupT

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.7200-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,426 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.501
• Publications: 0 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: Ambry Genetics, Orphanet, 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-132269711-T-TA is Benign according to our data. Variant chr9-132269711-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000868 (132/152140) while in subpopulation AMR AF = 0.00216 (33/15288). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	NM_015046.7	MANE Select	c.7200-10dupT		intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.7200-10dupT		intron	N/A	NP_001338457.1
	SETX	NM_001351527.2		c.7200-10dupT		intron	N/A	NP_001338456.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.7200-10_7200-9insT		intron	N/A	ENSP00000224140.5
	SETX	ENST00000436441.5	TSL:5	c.1926-10_1926-9insT		intron	N/A	ENSP00000409143.1
	SETX	ENST00000477049.1	TSL:3	n.227-10_227-9insT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000868 AC: 132 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00127

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00108 AC: 272 AN: 251414 AF XY: 0.00112

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00124 AC: 1814 AN: 1461286 Hom.: 2 Cov.: 31 AF XY: 0.00126 AC XY: 913 AN XY: 726964

African (AFR) AF: 0.000209 AC: 7 AN: 33470

American (AMR) AF: 0.00224 AC: 100 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00147 AC: 1630 AN: 1111512

Other (OTH) AF: 0.00118 AC: 71 AN: 60368

GnomAD4 genome AF: 0.000868 AC: 132 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.000901 AC XY: 67 AN XY: 74366

African (AFR) AF: 0.000241 AC: 10 AN: 41510

American (AMR) AF: 0.00216 AC: 33 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00127 AC: 86 AN: 67966

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000437 Hom.: 1

Bravo AF: 0.00121

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Hereditary spastic paraplegia (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		-0.50
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

Other links and lift over

dbSNP: rs531485265; hg19: chr9-135145098;