NM_015046.7:c.7100+182T>G

Variant names:

• chr9-132275074-A-C
• rs17148869
• NM_015046.7:c.7100+182T>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.7100+182T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 620,276 control chromosomes in the GnomAD database, including 10,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2636 hom., cov: 31)
  • Exomes 𝑓: 0.16 (8073 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.11
• Publications: 6 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 9-132275074-A-C is Benign according to our data. Variant chr9-132275074-A-C is described in ClinVar as Benign. ClinVar VariationId is 1295519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	NM_015046.7	MANE Select	c.7100+182T>G		intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.7100+182T>G		intron	N/A	NP_001338457.1
	SETX	NM_001351527.2		c.7100+182T>G		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.7100+182T>G		intron	N/A	ENSP00000224140.5
	SETX	ENST00000464133.1	TSL:2	n.480T>G		non_coding_transcript_exon	Exon 3 of 3
	SETX	ENST00000436441.5	TSL:5	c.1826+182T>G		intron	N/A	ENSP00000409143.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25562 AN: 151908 Hom.: 2634 Cov.: 31

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.157 AC: 73545 AN: 468250 Hom.: 8073 Cov.: 5 AF XY: 0.163 AC XY: 40506 AN XY: 249238

African (AFR) AF: 0.251 AC: 3173 AN: 12654

American (AMR) AF: 0.137 AC: 2688 AN: 19650

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 2723 AN: 14488

East Asian (EAS) AF: 0.460 AC: 14213 AN: 30916

South Asian (SAS) AF: 0.260 AC: 11764 AN: 45322

European-Finnish (FIN) AF: 0.120 AC: 3721 AN: 30992

Middle Eastern (MID) AF: 0.240 AC: 484 AN: 2018

European-Non Finnish (NFE) AF: 0.106 AC: 30342 AN: 285684

Other (OTH) AF: 0.167 AC: 4437 AN: 26526

GnomAD4 genome AF: 0.168 AC: 25591 AN: 152026 Hom.: 2636 Cov.: 31 AF XY: 0.173 AC XY: 12830 AN XY: 74306

African (AFR) AF: 0.242 AC: 10034 AN: 41438

American (AMR) AF: 0.141 AC: 2149 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 712 AN: 3468

East Asian (EAS) AF: 0.427 AC: 2205 AN: 5160

South Asian (SAS) AF: 0.281 AC: 1355 AN: 4814

European-Finnish (FIN) AF: 0.115 AC: 1223 AN: 10592

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7416 AN: 67972

Other (OTH) AF: 0.163 AC: 344 AN: 2106

Alfa AF: 0.135 Hom.: 5264

Bravo AF: 0.174

Asia WGS AF: 0.348 AC: 1207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.42
PhyloP100		-1.1
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: rs17148869; hg19: chr9-135150461;