NM_015046.7:c.498+20G>A

Variant names:

• chr9-132342670-C-T
• rs73659013
• NM_015046.7:c.498+20G>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.498+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,495,156 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (39 hom., cov: 32)
  • Exomes 𝑓: 0.019 (322 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.936
• Publications: 3 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 (BayesDel_noAF=-0.93).
• BP6: Variant 9-132342670-C-T is Benign according to our data. Variant chr9-132342670-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260507.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 = 0.0215 (3275/152264) while in subpopulation SAS AF = 0.04 (193/4824). AF 95% confidence interval is 0.0354. There are 39 homozygotes in GnomAd4. There are 1685 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 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.498+20G>A		intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.498+20G>A		intron	N/A	NP_001338457.1
	SETX	NM_001351527.2		c.498+20G>A		intron	N/A	NP_001338456.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.498+20G>A		intron	N/A	ENSP00000224140.5

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3274 AN: 152146 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00924

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.00980

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0212 AC: 5336 AN: 251200 AF XY: 0.0221

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.00674

Gnomad ASJ exome AF: 0.0360

Gnomad EAS exome AF: 0.0103

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0193 AC: 25926 AN: 1342892 Hom.: 322 Cov.: 20 AF XY: 0.0200 AC XY: 13526 AN XY: 675140

African (AFR) AF: 0.0260 AC: 810 AN: 31124

American (AMR) AF: 0.00682 AC: 304 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 880 AN: 25396

East Asian (EAS) AF: 0.0121 AC: 475 AN: 39154

South Asian (SAS) AF: 0.0392 AC: 3291 AN: 83932

European-Finnish (FIN) AF: 0.0310 AC: 1652 AN: 53252

Middle Eastern (MID) AF: 0.0233 AC: 129 AN: 5546

European-Non Finnish (NFE) AF: 0.0172 AC: 17221 AN: 1003366

Other (OTH) AF: 0.0206 AC: 1164 AN: 56536

GnomAD4 genome AF: 0.0215 AC: 3275 AN: 152264 Hom.: 39 Cov.: 32 AF XY: 0.0226 AC XY: 1685 AN XY: 74460

African (AFR) AF: 0.0256 AC: 1063 AN: 41536

American (AMR) AF: 0.00922 AC: 141 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3470

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5190

South Asian (SAS) AF: 0.0400 AC: 193 AN: 4824

European-Finnish (FIN) AF: 0.0340 AC: 361 AN: 10612

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0189 AC: 1289 AN: 68032

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.0219 Hom.: 7

Bravo AF: 0.0186

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Amyotrophic lateral sclerosis type 4 (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
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.50
DANN	Benign	0.42
PhyloP100		-0.94
Mutation Taster		=100/0	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: rs73659013; hg19: chr9-135218057; COSMIC: COSV56381102;