rs116333061

Variant names:

• chr9-132329641-G-T
• rs116333061
• NM_015046.7:c.1957C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015046.7(SETX):​c.1957C>A​(p.Gln653Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,660 control chromosomes in the GnomAD database, including 16 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (9 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.21
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042258054).
• BP6: Variant 9-132329641-G-T is Benign according to our data. Variant chr9-132329641-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00592 (901/152238) while in subpopulation AFR AF = 0.0201 (837/41540). AF 95% confidence interval is 0.019. There are 7 homozygotes in GnomAd4. There are 442 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.1957C>A	p.Gln653Lys	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.1957C>A	p.Gln653Lys	missense	Exon 10 of 27	NP_001338457.1
	SETX	NM_001351527.2		c.1957C>A	p.Gln653Lys	missense	Exon 10 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.1957C>A	p.Gln653Lys	missense	Exon 10 of 26	ENSP00000224140.5
	SETX	ENST00000923216.1		c.1957C>A	p.Gln653Lys	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.1957C>A	p.Gln653Lys	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00592 AC: 901 AN: 152120 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00149 AC: 373 AN: 250516 AF XY: 0.00117

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000621 AC: 907 AN: 1461422 Hom.: 9 Cov.: 35 AF XY: 0.000539 AC XY: 392 AN XY: 726994

African (AFR) AF: 0.0218 AC: 727 AN: 33418

American (AMR) AF: 0.00134 AC: 60 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111916

Other (OTH) AF: 0.00141 AC: 85 AN: 60378

GnomAD4 genome AF: 0.00592 AC: 901 AN: 152238 Hom.: 7 Cov.: 33 AF XY: 0.00594 AC XY: 442 AN XY: 74444

African (AFR) AF: 0.0201 AC: 837 AN: 41540

American (AMR) AF: 0.00314 AC: 48 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00205 Hom.: 11

Bravo AF: 0.00720

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Hereditary 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	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.40	T
Polyphen		0.44	B
Vest4		0.23
MVP		0.64
MPC		0.12
ClinPred		0.011	T
GERP RS		4.2
Varity_R		0.10
gMVP		0.21
Mutation Taster		=84/16	polymorphism

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: rs116333061; hg19: chr9-135205028;