9-132298298-T-C

Variant names:

• chr9-132298298-T-C
• rs2296871
• NM_015046.7:c.5563A>G
• SETX p.Thr1855Ala

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015046.7(SETX):​c.5563A>G​(p.Thr1855Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,270 control chromosomes in the GnomAD database, including 51,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (11057 hom., cov: 33)
  • Exomes 𝑓: 0.20 (40693 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.716
• Publications: 45 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5498156E-6).
• BP6: Variant 9-132298298-T-C is Benign according to our data. Variant chr9-132298298-T-C is described in ClinVar as Benign. ClinVar VariationId is 95665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.657 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.5563A>G	p.Thr1855Ala	missense	Exon 13 of 26	NP_055861.3
	SETX	NM_001351528.2		c.5563A>G	p.Thr1855Ala	missense	Exon 13 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.5563A>G	p.Thr1855Ala	missense	Exon 13 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.5563A>G	p.Thr1855Ala	missense	Exon 13 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.5563A>G	p.Thr1855Ala	missense	Exon 13 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.5563A>G	p.Thr1855Ala	missense	Exon 13 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48237 AN: 152030 Hom.: 11015 Cov.: 33

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.266 AC: 66814 AN: 251216 AF XY: 0.261

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.199 AC: 290334 AN: 1460122 Hom.: 40693 Cov.: 33 AF XY: 0.203 AC XY: 147124 AN XY: 726470

African (AFR) AF: 0.632 AC: 21118 AN: 33406

American (AMR) AF: 0.207 AC: 9240 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6610 AN: 26118

East Asian (EAS) AF: 0.713 AC: 28268 AN: 39672

South Asian (SAS) AF: 0.362 AC: 31182 AN: 86186

European-Finnish (FIN) AF: 0.169 AC: 9013 AN: 53406

Middle Eastern (MID) AF: 0.342 AC: 1971 AN: 5768

European-Non Finnish (NFE) AF: 0.151 AC: 168146 AN: 1110526

Other (OTH) AF: 0.245 AC: 14786 AN: 60318

GnomAD4 genome AF: 0.318 AC: 48333 AN: 152148 Hom.: 11057 Cov.: 33 AF XY: 0.320 AC XY: 23801 AN XY: 74376

African (AFR) AF: 0.616 AC: 25539 AN: 41476

American (AMR) AF: 0.215 AC: 3284 AN: 15290

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

East Asian (EAS) AF: 0.676 AC: 3499 AN: 5176

South Asian (SAS) AF: 0.380 AC: 1834 AN: 4826

European-Finnish (FIN) AF: 0.169 AC: 1787 AN: 10576

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.157 AC: 10667 AN: 68012

Other (OTH) AF: 0.276 AC: 583 AN: 2116

Alfa AF: 0.227 Hom.: 13804

Bravo AF: 0.335

Asia WGS AF: 0.506 AC: 1761 AN: 3478

EpiCase AF: 0.161

EpiControl AF: 0.167

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.5
DANN	Benign	0.30
DEOGEN2	Benign	0.11	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.72
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.21
Sift	Benign	0.83	T
Sift4G	Benign	0.58	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.21
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2296871;

hg19: chr9-135173685;

COSMIC: COSV56380996;