rs3739922

Variant names:

• chr9-132328143-A-C
• rs3739922
• NM_015046.7:c.3455T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015046.7(SETX):​c.3455T>G​(p.Phe1152Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,613,922 control chromosomes in the GnomAD database, including 2,842 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1152L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.050 (318 hom., cov: 32)
  • Exomes 𝑓: 0.045 (2524 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.30
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027791858).
• BP6: Variant 9-132328143-A-C is Benign according to our data. Variant chr9-132328143-A-C is described in ClinVar as Benign. ClinVar VariationId is 95660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

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.3455T>G	p.Phe1152Cys	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.3455T>G	p.Phe1152Cys	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.3455T>G	p.Phe1152Cys	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.3455T>G	p.Phe1152Cys	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.3455T>G	p.Phe1152Cys	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.3455T>G	p.Phe1152Cys	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7611 AN: 152068 Hom.: 319 Cov.: 32

Gnomad AFR AF: 0.0503

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.0734

Gnomad FIN AF: 0.0480

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0412

GnomAD2 exomes AF: 0.0652 AC: 16354 AN: 250992 AF XY: 0.0633

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.0695

Gnomad ASJ exome AF: 0.0331

Gnomad EAS exome AF: 0.271

Gnomad FIN exome AF: 0.0553

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0480

GnomAD4 exome AF: 0.0451 AC: 65868 AN: 1461736 Hom.: 2524 Cov.: 37 AF XY: 0.0456 AC XY: 33123 AN XY: 727158

African (AFR) AF: 0.0482 AC: 1613 AN: 33456

American (AMR) AF: 0.0662 AC: 2960 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 921 AN: 26130

East Asian (EAS) AF: 0.247 AC: 9819 AN: 39688

South Asian (SAS) AF: 0.0710 AC: 6120 AN: 86224

European-Finnish (FIN) AF: 0.0538 AC: 2873 AN: 53418

Middle Eastern (MID) AF: 0.0465 AC: 268 AN: 5768

European-Non Finnish (NFE) AF: 0.0345 AC: 38361 AN: 1111976

Other (OTH) AF: 0.0486 AC: 2933 AN: 60384

GnomAD4 genome AF: 0.0500 AC: 7615 AN: 152186 Hom.: 318 Cov.: 32 AF XY: 0.0514 AC XY: 3824 AN XY: 74406

African (AFR) AF: 0.0503 AC: 2090 AN: 41518

American (AMR) AF: 0.0476 AC: 728 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.256 AC: 1325 AN: 5184

South Asian (SAS) AF: 0.0735 AC: 354 AN: 4818

European-Finnish (FIN) AF: 0.0480 AC: 508 AN: 10584

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0347 AC: 2363 AN: 68006

Other (OTH) AF: 0.0398 AC: 84 AN: 2110

Alfa AF: 0.0442 Hom.: 934

Bravo AF: 0.0520

TwinsUK AF: 0.0361 AC: 134

ALSPAC AF: 0.0348 AC: 134

ESP6500AA AF: 0.0479 AC: 211

ESP6500EA AF: 0.0336 AC: 289

ExAC AF: 0.0655 AC: 7958

Asia WGS AF: 0.136 AC: 473 AN: 3478

EpiCase AF: 0.0317

EpiControl AF: 0.0325

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	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	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.14	T
Polyphen		0.0030	B
Vest4		0.060
MPC		0.11
ClinPred		0.014	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.32
Mutation Taster		=84/16	polymorphism (auto)

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: rs3739922; hg19: chr9-135203530; COSMIC: COSV56381024;