rs144334281

Variant names:

• chr9-132327789-G-A
• rs144334281
• NM_015046.7:c.3809C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132327789-G-A
• chr9-132327789-G-C

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.3809C>T​(p.Pro1270Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000947 in 1,614,088 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. P1270P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (3 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 5.07
• Publications: 5 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=0.008942604).
• BP6: Variant 9-132327789-G-A is Benign according to our data. Variant chr9-132327789-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242634.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00116 (176/152208) while in subpopulation NFE AF = 0.000926 (63/68008). AF 95% confidence interval is 0.000742. There are 0 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.3809C>T	p.Pro1270Leu	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.3809C>T	p.Pro1270Leu	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.3809C>T	p.Pro1270Leu	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.3809C>T	p.Pro1270Leu	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.3809C>T	p.Pro1270Leu	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.3809C>T	p.Pro1270Leu	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00916

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00119 AC: 299 AN: 251434 AF XY: 0.00116

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000925 AC: 1352 AN: 1461880 Hom.: 3 Cov.: 65 AF XY: 0.000954 AC XY: 694 AN XY: 727236

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86256

European-Finnish (FIN) AF: 0.00736 AC: 393 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000775 AC: 862 AN: 1112010

Other (OTH) AF: 0.000745 AC: 45 AN: 60396

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74422

African (AFR) AF: 0.000217 AC: 9 AN: 41534

American (AMR) AF: 0.000196 AC: 3 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00916 AC: 97 AN: 10586

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

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68008

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

Alfa AF: 0.000919 Hom.: 0

Bravo AF: 0.000480

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00125 AC: 152

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Inborn genetic diseases (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	0.22
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.0089	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.90	P
Vest4		0.17
MVP		0.91
MPC		0.13
ClinPred		0.062	T
GERP RS		4.0
Varity_R		0.20
gMVP		0.19
Mutation Taster		=89/11	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: rs144334281; hg19: chr9-135203176; COSMIC: COSV99808703;