rs145097270

Variant names:

• chr9-132328369-C-T
• rs145097270
• NM_015046.7:c.3229G>A

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.3229G>A​(p.Asp1077Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,032 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:8
• Conservation: PhyloP100: 4.08
• Publications: 12 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=0.013518751).
• BP6: Variant 9-132328369-C-T is Benign according to our data. Variant chr9-132328369-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 424687.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00108 (164/152300) while in subpopulation AMR AF = 0.00359 (55/15302). AF 95% confidence interval is 0.00284. There are 1 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.3229G>A	p.Asp1077Asn	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.3229G>A	p.Asp1077Asn	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.3229G>A	p.Asp1077Asn	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.3229G>A	p.Asp1077Asn	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.3229G>A	p.Asp1077Asn	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.3229G>A	p.Asp1077Asn	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00125 AC: 314 AN: 251092 AF XY: 0.00133

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00116 AC: 1702 AN: 1461732 Hom.: 8 Cov.: 37 AF XY: 0.00119 AC XY: 864 AN XY: 727164

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.00125 AC: 56 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00425 AC: 111 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00202 AC: 174 AN: 86252

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53320

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5768

European-Non Finnish (NFE) AF: 0.00105 AC: 1173 AN: 1111980

Other (OTH) AF: 0.00121 AC: 73 AN: 60394

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74472

African (AFR) AF: 0.000192 AC: 8 AN: 41566

American (AMR) AF: 0.00359 AC: 55 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00129 Hom.: 3

Bravo AF: 0.00112

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00110 AC: 133

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00218

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
1	-	-	Amyotrophic lateral sclerosis (1)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (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	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.028	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.93	P
Vest4		0.12
MVP		0.81
MPC		0.11
ClinPred		0.16	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.24
gMVP		0.31
Mutation Taster		=92/8	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: rs145097270; hg19: chr9-135203756; COSMIC: COSV56385421;