rs150532677

Variant names:

• chr9-132329119-T-C
• rs150532677
• NM_015046.7:c.2479A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_015046.7(SETX):​c.2479A>G​(p.Lys827Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00099 in 1,610,188 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:9
• Conservation: PhyloP100: 0.448
• Publications: 6 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023649603).
• BP6: Variant 9-132329119-T-C is Benign according to our data. Variant chr9-132329119-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468494.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000591 (90/152364) while in subpopulation NFE AF = 0.00101 (69/68034). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.2479A>G	p.Lys827Glu	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.2479A>G	p.Lys827Glu	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.2479A>G	p.Lys827Glu	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.2479A>G	p.Lys827Glu	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.2479A>G	p.Lys827Glu	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.2479A>G	p.Lys827Glu	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000844 AC: 208 AN: 246404 AF XY: 0.000915

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.000643

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.00103 AC: 1504 AN: 1457824 Hom.: 1 Cov.: 36 AF XY: 0.00103 AC XY: 746 AN XY: 725216

African (AFR) AF: 0.000180 AC: 6 AN: 33358

American (AMR) AF: 0.000450 AC: 20 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39636

South Asian (SAS) AF: 0.00126 AC: 108 AN: 85766

European-Finnish (FIN) AF: 0.000489 AC: 25 AN: 51156

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5756

European-Non Finnish (NFE) AF: 0.00115 AC: 1276 AN: 1111358

Other (OTH) AF: 0.000995 AC: 60 AN: 60300

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74508

African (AFR) AF: 0.000168 AC: 7 AN: 41580

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000935 Hom.: 2

Bravo AF: 0.000604

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	2	not specified (3)
-	2	-	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	1	-	Amyotrophic lateral sclerosis type 4 (1)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	See cases (1)
-	-	1	SETX-related disorder (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	0.088
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.45
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.29
Sift	Benign	0.057	T
Sift4G	Benign	0.092	T
Polyphen		0.73	P
Vest4		0.31
MVP		0.76
MPC		0.11
ClinPred		0.080	T
GERP RS		5.7
Varity_R		0.15
gMVP		0.17
Mutation Taster		=83/17	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: rs150532677; hg19: chr9-135204506;