rs116205032

Variant names:

• chr9-132329791-T-C
• rs116205032
• NM_015046.7:c.1807A>G

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.1807A>G​(p.Asn603Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000837 in 1,614,034 control chromosomes in the GnomAD database, including 9 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N603S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (5 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.35
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02440682).
• BP6: Variant 9-132329791-T-C is Benign according to our data. Variant chr9-132329791-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446186.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 = 0.00446 (679/152340) while in subpopulation AFR AF = 0.0156 (649/41578). AF 95% confidence interval is 0.0146. There are 4 homozygotes in GnomAd4. There are 328 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1807A>G	p.Asn603Asp	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.1807A>G	p.Asn603Asp	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.1807A>G	p.Asn603Asp	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.1807A>G	p.Asn603Asp	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.1807A>G	p.Asn603Asp	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.1807A>G	p.Asn603Asp	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152222 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00102 AC: 257 AN: 250898 AF XY: 0.000782

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000460 AC: 672 AN: 1461694 Hom.: 5 Cov.: 35 AF XY: 0.000393 AC XY: 286 AN XY: 727164

African (AFR) AF: 0.0172 AC: 575 AN: 33434

American (AMR) AF: 0.000671 AC: 30 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111962

Other (OTH) AF: 0.000960 AC: 58 AN: 60386

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152340 Hom.: 4 Cov.: 33 AF XY: 0.00440 AC XY: 328 AN XY: 74508

African (AFR) AF: 0.0156 AC: 649 AN: 41578

American (AMR) AF: 0.00131 AC: 20 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00159 Hom.: 9

Bravo AF: 0.00539

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 143

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

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	not specified (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	0.093
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.26
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.027	D
Polyphen		0.16	B
Vest4		0.093
MVP		0.58
MPC		0.10
ClinPred		0.018	T
GERP RS		4.5
Varity_R		0.085
gMVP		0.087
Mutation Taster		=81/19	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: rs116205032; hg19: chr9-135205178;