9-132297025-A-G

Variant names:

• chr9-132297025-A-G
• rs2296869
• NM_015046.7:c.5811T>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.5811T>C​(p.Asp1937Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,012 control chromosomes in the GnomAD database, including 51,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (11023 hom., cov: 32)
  • Exomes 𝑓: 0.20 (40460 hom.)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.690
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 9-132297025-A-G is Benign according to our data. Variant chr9-132297025-A-G is described in ClinVar as Benign. ClinVar VariationId is 95667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 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.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 26	NP_055861.3
	SETX	NM_001351528.2		c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 27	NP_001338457.1
	SETX	NM_001351527.2		c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 26	NP_001338456.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 26	ENSP00000224140.5
	SETX	ENST00000923216.1		c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48155 AN: 151882 Hom.: 10981 Cov.: 32

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.274

GnomAD2 exomes AF: 0.265 AC: 66348 AN: 249954 AF XY: 0.260

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.689

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.199 AC: 290173 AN: 1460014 Hom.: 40460 Cov.: 32 AF XY: 0.202 AC XY: 147009 AN XY: 726382

African (AFR) AF: 0.632 AC: 21121 AN: 33432

American (AMR) AF: 0.206 AC: 9210 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6608 AN: 26104

East Asian (EAS) AF: 0.706 AC: 28001 AN: 39668

South Asian (SAS) AF: 0.362 AC: 31144 AN: 86146

European-Finnish (FIN) AF: 0.169 AC: 8980 AN: 53292

Middle Eastern (MID) AF: 0.342 AC: 1969 AN: 5764

European-Non Finnish (NFE) AF: 0.152 AC: 168358 AN: 1110656

Other (OTH) AF: 0.245 AC: 14782 AN: 60320

GnomAD4 genome AF: 0.317 AC: 48251 AN: 151998 Hom.: 11023 Cov.: 32 AF XY: 0.320 AC XY: 23733 AN XY: 74266

African (AFR) AF: 0.616 AC: 25524 AN: 41446

American (AMR) AF: 0.214 AC: 3266 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 922 AN: 3472

East Asian (EAS) AF: 0.670 AC: 3463 AN: 5166

South Asian (SAS) AF: 0.380 AC: 1829 AN: 4818

European-Finnish (FIN) AF: 0.169 AC: 1784 AN: 10562

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10665 AN: 67952

Other (OTH) AF: 0.275 AC: 580 AN: 2108

Alfa AF: 0.220 Hom.: 4987

Bravo AF: 0.335

Asia WGS AF: 0.503 AC: 1750 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.58
CADD	Benign	7.0
DANN	Benign	0.46
PhyloP100		0.69
Mutation Taster		=97/3	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: rs2296869; hg19: chr9-135172412; COSMIC: COSV56380974;