rs9411449

Variant names:

• chr9-132331073-A-G
• rs9411449
• NM_015046.7:c.1077T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015046.7(SETX):​c.1077T>C​(p.Tyr359Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 1,611,662 control chromosomes in the GnomAD database, including 531,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (44091 hom., cov: 32)
  • Exomes 𝑓: 0.81 (487094 hom.)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.351
• Publications: 25 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-132331073-A-G is Benign according to our data. Variant chr9-132331073-A-G is described in ClinVar as Benign. ClinVar VariationId is 95658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.351 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

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.1077T>C	p.Tyr359Tyr	synonymous	Exon 9 of 26	NP_055861.3
	SETX	NM_001351528.2		c.1077T>C	p.Tyr359Tyr	synonymous	Exon 9 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.1077T>C	p.Tyr359Tyr	synonymous	Exon 9 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.1077T>C	p.Tyr359Tyr	synonymous	Exon 9 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.1077T>C	p.Tyr359Tyr	synonymous	Exon 9 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.1077T>C	p.Tyr359Tyr	synonymous	Exon 9 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.750 AC: 114024 AN: 151968 Hom.: 44069 Cov.: 32

Gnomad AFR AF: 0.619

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.845

Gnomad OTH AF: 0.771

GnomAD2 exomes AF: 0.752 AC: 188932 AN: 251112 AF XY: 0.753

Gnomad AFR exome AF: 0.617

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.748

Gnomad EAS exome AF: 0.308

Gnomad FIN exome AF: 0.832

Gnomad NFE exome AF: 0.842

Gnomad OTH exome AF: 0.784

GnomAD4 exome AF: 0.810 AC: 1181901 AN: 1459576 Hom.: 487094 Cov.: 39 AF XY: 0.805 AC XY: 584694 AN XY: 726210

African (AFR) AF: 0.606 AC: 20281 AN: 33440

American (AMR) AF: 0.807 AC: 36071 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 19501 AN: 26110

East Asian (EAS) AF: 0.317 AC: 12559 AN: 39664

South Asian (SAS) AF: 0.638 AC: 55044 AN: 86214

European-Finnish (FIN) AF: 0.832 AC: 44356 AN: 53344

Middle Eastern (MID) AF: 0.673 AC: 3870 AN: 5752

European-Non Finnish (NFE) AF: 0.850 AC: 943642 AN: 1110008

Other (OTH) AF: 0.772 AC: 46577 AN: 60324

GnomAD4 genome AF: 0.750 AC: 114096 AN: 152086 Hom.: 44091 Cov.: 32 AF XY: 0.744 AC XY: 55341 AN XY: 74338

African (AFR) AF: 0.618 AC: 25624 AN: 41430

American (AMR) AF: 0.808 AC: 12362 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 2550 AN: 3472

East Asian (EAS) AF: 0.333 AC: 1724 AN: 5172

South Asian (SAS) AF: 0.620 AC: 2990 AN: 4820

European-Finnish (FIN) AF: 0.831 AC: 8781 AN: 10566

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.845 AC: 57453 AN: 68016

Other (OTH) AF: 0.769 AC: 1622 AN: 2108

Alfa AF: 0.808 Hom.: 174311

Bravo AF: 0.742

Asia WGS AF: 0.507 AC: 1763 AN: 3478

EpiCase AF: 0.840

EpiControl AF: 0.834

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	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
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.4
DANN	Benign	0.36
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs9411449; hg19: chr9-135206460; COSMIC: COSV56380923;