rs145438764

Variant names:

• chr9-132342716-A-C
• rs145438764
• NM_015046.7:c.472T>G

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.472T>G​(p.Leu158Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 1,613,718 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L158L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 1.75
• Publications: 15 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=0.019678175).
• BP6: Variant 9-132342716-A-C is Benign according to our data. Variant chr9-132342716-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 365376.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00347 (529/152276) while in subpopulation NFE AF = 0.00542 (369/68024). AF 95% confidence interval is 0.00497. There are 0 homozygotes in GnomAd4. There are 276 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 27 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.472T>G	p.Leu158Val	missense	Exon 5 of 26	NP_055861.3
	SETX	NM_001351528.2		c.472T>G	p.Leu158Val	missense	Exon 5 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.472T>G	p.Leu158Val	missense	Exon 5 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.472T>G	p.Leu158Val	missense	Exon 5 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.472T>G	p.Leu158Val	missense	Exon 5 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.472T>G	p.Leu158Val	missense	Exon 5 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00542

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00375 AC: 943 AN: 251412 AF XY: 0.00396

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00426

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00488 AC: 7132 AN: 1461442 Hom.: 27 Cov.: 31 AF XY: 0.00497 AC XY: 3610 AN XY: 727072

African (AFR) AF: 0.000747 AC: 25 AN: 33474

American (AMR) AF: 0.00152 AC: 68 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00408 AC: 352 AN: 86248

European-Finnish (FIN) AF: 0.00455 AC: 243 AN: 53380

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.00552 AC: 6131 AN: 1111654

Other (OTH) AF: 0.00381 AC: 230 AN: 60374

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00371 AC XY: 276 AN XY: 74438

African (AFR) AF: 0.000890 AC: 37 AN: 41564

American (AMR) AF: 0.000785 AC: 12 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4824

European-Finnish (FIN) AF: 0.00697 AC: 74 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00542 AC: 369 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00495 Hom.: 4

Bravo AF: 0.00304

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00371 AC: 450

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)
-	-	2	not specified (2)
-	-	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	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	0.28
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MVP		0.73
MPC		0.43
ClinPred		0.024	T
GERP RS		-0.026
Varity_R		0.34
gMVP		0.51
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145438764; hg19: chr9-135218103;