9-132328623-T-C

Variant names:

• chr9-132328623-T-C
• rs61742937
• NM_015046.7:c.2975A>G
• SETX p.Lys992Arg

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015046.7(SETX):​c.2975A>G​(p.Lys992Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,490 control chromosomes in the GnomAD database, including 252 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K992Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 33)
  • Exomes 𝑓: 0.015 (229 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 1.08
• Publications: 17 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022610426).
• BP6: Variant 9-132328623-T-C is Benign according to our data. Variant chr9-132328623-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260502.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0141 (2151/152308) while in subpopulation NFE AF = 0.0175 (1189/68026). AF 95% confidence interval is 0.0167. There are 23 homozygotes in GnomAd4. There are 1102 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR,AD gene

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.2975A>G	p.Lys992Arg	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.2975A>G	p.Lys992Arg	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.2975A>G	p.Lys992Arg	missense	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.2975A>G	p.Lys992Arg	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.2975A>G	p.Lys992Arg	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.2975A>G	p.Lys992Arg	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2155 AN: 152190 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0505

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0152 AC: 3812 AN: 250468 AF XY: 0.0160

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.00778

Gnomad ASJ exome AF: 0.00747

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0145 AC: 21237 AN: 1461182 Hom.: 229 Cov.: 36 AF XY: 0.0148 AC XY: 10739 AN XY: 726898

African (AFR) AF: 0.00230 AC: 77 AN: 33434

American (AMR) AF: 0.00823 AC: 367 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00732 AC: 191 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00705 AC: 607 AN: 86158

European-Finnish (FIN) AF: 0.0468 AC: 2497 AN: 53362

Middle Eastern (MID) AF: 0.0130 AC: 75 AN: 5768

European-Non Finnish (NFE) AF: 0.0150 AC: 16621 AN: 1111706

Other (OTH) AF: 0.0133 AC: 801 AN: 60350

GnomAD4 genome AF: 0.0141 AC: 2151 AN: 152308 Hom.: 23 Cov.: 33 AF XY: 0.0148 AC XY: 1102 AN XY: 74468

African (AFR) AF: 0.00257 AC: 107 AN: 41576

American (AMR) AF: 0.0142 AC: 217 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4828

European-Finnish (FIN) AF: 0.0505 AC: 535 AN: 10594

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0175 AC: 1189 AN: 68026

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.0145 Hom.: 38

Bravo AF: 0.0113

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Hereditary spastic paraplegia (1)
-	1	-	Spastic paraplegia (1)
-	-	1	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (1)
-	-	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	0.081
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Benign	0.039	D
Sift4G	Benign	0.081	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.24
Mutation Taster		=88/12	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: rs61742937;

hg19: chr9-135204010;