9-132261855-A-T

Variant names:

• chr9-132261855-A-T
• rs570456500
• NM_015046.7:c.*2384T>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015046.7(SETX):​c.*2384T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 154,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (0 hom.)
• Consequence: SETX NM_015046.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.753
• 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: 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00023 (35/152334) while in subpopulation AMR AF = 0.000915 (14/15302). AF 95% confidence interval is 0.000553. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*2384T>A		3_prime_UTR	Exon 26 of 26	NP_055861.3
	SETX	NM_001351528.2		c.*2384T>A		3_prime_UTR	Exon 27 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.*2384T>A		3_prime_UTR	Exon 26 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.*2384T>A		3_prime_UTR	Exon 26 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.*2384T>A		3_prime_UTR	Exon 28 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.*2384T>A		3_prime_UTR	Exon 27 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.000191

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00253 AC: 6 AN: 2374 Hom.: 0 Cov.: 0 AF XY: 0.00251 AC XY: 3 AN XY: 1194

African (AFR) AF: 0.00 AC: 0 AN: 74

American (AMR) AF: 0.00 AC: 0 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 94

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 194

Middle Eastern (MID) AF: 0.00245 AC: 4 AN: 1632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 178

Other (OTH) AF: 0.0105 AC: 2 AN: 190

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74496

African (AFR) AF: 0.000168 AC: 7 AN: 41570

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.000295

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Amyotrophic lateral sclerosis type 4 (1)
-	1	-	not provided (1)
-	1	-	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.5
DANN	Benign	0.82
PhyloP100		-0.75
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: rs570456500; hg19: chr9-135137242;