rs79740039

Variant names:

• chr9-132349370-C-T
• rs79740039
• NM_015046.7:c.59G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015046.7(SETX):​c.59G>A​(p.Arg20His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00853 in 1,614,102 control chromosomes in the GnomAD database, including 94 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (89 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.510
• Publications: 18 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: Ambry Genetics, Orphanet, 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004255116).
• BP6: Variant 9-132349370-C-T is Benign according to our data. Variant chr9-132349370-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 242635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00636 (968/152210) while in subpopulation SAS AF = 0.0153 (74/4824). AF 95% confidence interval is 0.0125. There are 5 homozygotes in GnomAd4. There are 496 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	NM_015046.7	MANE Select	c.59G>A	p.Arg20His	missense	Exon 3 of 26	NP_055861.3
	SETX	NM_001351528.2		c.59G>A	p.Arg20His	missense	Exon 3 of 27	NP_001338457.1
	SETX	NM_001351527.2		c.59G>A	p.Arg20His	missense	Exon 3 of 26	NP_001338456.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.59G>A	p.Arg20His	missense	Exon 3 of 26	ENSP00000224140.5

Frequencies

GnomAD3 genomes AF: 0.00636 AC: 968 AN: 152092 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00842

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00924 AC: 2325 AN: 251488 AF XY: 0.00978

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0160

Gnomad NFE exome AF: 0.00944

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00875 AC: 12794 AN: 1461892 Hom.: 89 Cov.: 32 AF XY: 0.00912 AC XY: 6633 AN XY: 727246

African (AFR) AF: 0.00102 AC: 34 AN: 33480

American (AMR) AF: 0.00420 AC: 188 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 387 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0171 AC: 1474 AN: 86258

European-Finnish (FIN) AF: 0.0148 AC: 789 AN: 53420

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.00839 AC: 9326 AN: 1112010

Other (OTH) AF: 0.00886 AC: 535 AN: 60396

GnomAD4 genome AF: 0.00636 AC: 968 AN: 152210 Hom.: 5 Cov.: 32 AF XY: 0.00666 AC XY: 496 AN XY: 74430

African (AFR) AF: 0.00106 AC: 44 AN: 41514

American (AMR) AF: 0.00399 AC: 61 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4824

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10606

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00842 AC: 573 AN: 68012

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00788 Hom.: 24

Bravo AF: 0.00535

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00906 AC: 1100

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.00878

EpiControl AF: 0.00936

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	SETX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.6
DANN	Benign	0.92
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.51
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.16
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.15
MVP		0.45
MPC		0.092
ClinPred		0.0012	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.13
Mutation Taster		=95/5	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: rs79740039; hg19: chr9-135224757; COSMIC: COSV99808683;