rs151117904

Variant names:

• chr9-132264633-A-G
• rs151117904
• NM_015046.7:c.7640T>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.7640T>C​(p.Ile2547Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,614,206 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (25 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 0.238
• Publications: 28 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=0.0033735633).
• BP6: Variant 9-132264633-A-G is Benign according to our data. Variant chr9-132264633-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 155748.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00428 (652/152312) while in subpopulation AMR AF = 0.0122 (186/15300). AF 95% confidence interval is 0.0107. There are 4 homozygotes in GnomAd4. There are 310 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.7640T>C	p.Ile2547Thr	missense	Exon 26 of 26	NP_055861.3
	SETX	NM_001351528.2		c.7727T>C	p.Ile2576Thr	missense	Exon 27 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.7640T>C	p.Ile2547Thr	missense	Exon 26 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.7640T>C	p.Ile2547Thr	missense	Exon 26 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.7766T>C	p.Ile2589Thr	missense	Exon 28 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.7679T>C	p.Ile2560Thr	missense	Exon 27 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 652 AN: 152192 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00391 AC: 983 AN: 251496 AF XY: 0.00386

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00572

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00518 AC: 7573 AN: 1461894 Hom.: 25 Cov.: 32 AF XY: 0.00512 AC XY: 3722 AN XY: 727248

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00691 AC: 309 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00122 AC: 105 AN: 86258

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53420

Middle Eastern (MID) AF: 0.0107 AC: 62 AN: 5768

European-Non Finnish (NFE) AF: 0.00602 AC: 6698 AN: 1112012

Other (OTH) AF: 0.00536 AC: 324 AN: 60396

GnomAD4 genome AF: 0.00428 AC: 652 AN: 152312 Hom.: 4 Cov.: 32 AF XY: 0.00416 AC XY: 310 AN XY: 74480

African (AFR) AF: 0.00149 AC: 62 AN: 41554

American (AMR) AF: 0.0122 AC: 186 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 68032

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00496 Hom.: 4

Bravo AF: 0.00532

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00342 AC: 415

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00581

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	4	not specified (4)
-	1	-	Amyotrophic lateral sclerosis (1)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	Hereditary spastic paraplegia (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	0.061
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.70
DANN	Benign	0.39
DEOGEN2	Benign	0.093	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.24
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.11
Sift	Benign	0.32	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.044
MVP		0.43
MPC		0.093
ClinPred		0.00057	T
GERP RS		-3.4
Varity_R		0.017
gMVP		0.12
Mutation Taster		=99/1	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: rs151117904; hg19: chr9-135140020; COSMIC: COSV105039712;