rs148181729

Variant names:

• chr9-132328926-A-G
• rs148181729
• NM_015046.7:c.2672T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-132328926-A-G
• chr9-132328926-A-T

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.2672T>C​(p.Val891Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,613,006 control chromosomes in the GnomAD database, including 8 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (3 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -0.765
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003240317).
• BP6: Variant 9-132328926-A-G is Benign according to our data. Variant chr9-132328926-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 365364.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00429 (653/152362) while in subpopulation AFR AF = 0.0147 (612/41592). AF 95% confidence interval is 0.0137. There are 5 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.2672T>C	p.Val891Ala	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.2672T>C	p.Val891Ala	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.2672T>C	p.Val891Ala	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.2672T>C	p.Val891Ala	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.2672T>C	p.Val891Ala	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.2672T>C	p.Val891Ala	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 652 AN: 152244 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00113 AC: 283 AN: 249526 AF XY: 0.000957

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000634 AC: 926 AN: 1460644 Hom.: 3 Cov.: 36 AF XY: 0.000593 AC XY: 431 AN XY: 726564

African (AFR) AF: 0.0168 AC: 561 AN: 33438

American (AMR) AF: 0.00110 AC: 49 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

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

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85916

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53150

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000192 AC: 214 AN: 1111698

Other (OTH) AF: 0.00126 AC: 76 AN: 60358

GnomAD4 genome AF: 0.00429 AC: 653 AN: 152362 Hom.: 5 Cov.: 33 AF XY: 0.00419 AC XY: 312 AN XY: 74504

African (AFR) AF: 0.0147 AC: 612 AN: 41592

American (AMR) AF: 0.00118 AC: 18 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68038

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00147 Hom.: 3

Bravo AF: 0.00488

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Hereditary spastic paraplegia (1)
-	1	-	Neuronopathy, distal hereditary motor, autosomal dominant (1)
-	-	1	SETX-related disorder (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	0.071
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.11
DANN	Benign	0.70
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.26	N
PhyloP100		-0.77
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.18
Sift	Benign	0.60	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.052
MVP		0.43
MPC		0.089
ClinPred		0.00028	T
GERP RS		-2.0
Varity_R		0.036
gMVP		0.10
Mutation Taster		=100/0	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: rs148181729; hg19: chr9-135204313;