9-132330207-G-T

Variant names:

• chr9-132330207-G-T
• rs200614765
• NM_015046.7:c.1391C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_015046.7(SETX):​c.1391C>A​(p.Ser464*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000704 in 1,420,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S464S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SETX NM_015046.7 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.80
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.1391C>A	p.Ser464*	stop_gained	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.1391C>A	p.Ser464*	stop_gained	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.1391C>A	p.Ser464*	stop_gained	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.1391C>A	p.Ser464*	stop_gained	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.1391C>A	p.Ser464*	stop_gained	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.1391C>A	p.Ser464*	stop_gained	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420108 Hom.: 0 Cov.: 35 AF XY: 0.00000143 AC XY: 1 AN XY: 701546

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32002

American (AMR) AF: 0.0000256 AC: 1 AN: 39122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23508

East Asian (EAS) AF: 0.00 AC: 0 AN: 39224

South Asian (SAS) AF: 0.00 AC: 0 AN: 79390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090982

Other (OTH) AF: 0.00 AC: 0 AN: 58428

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		4.8
Vest4		0.71
GERP RS		5.7
Mutation Taster		=0/200	disease causing (fs/PTC)

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: rs200614765; hg19: chr9-135205594;