9-132278281-C-T

Variant names:

• chr9-132278281-C-T
• rs11243704
• NM_015046.7:c.6655-24G>A

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.6655-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,611,106 control chromosomes in the GnomAD database, including 102,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (17939 hom., cov: 30)
  • Exomes 𝑓: 0.32 (84594 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.881
• Publications: 15 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 (BayesDel_noAF=-0.91).
• BP6: Variant 9-132278281-C-T is Benign according to our data. Variant chr9-132278281-C-T is described in ClinVar as Benign. ClinVar VariationId is 260513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 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.6655-24G>A		intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.6655-24G>A		intron	N/A	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.6655-24G>A		intron	N/A	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.6655-24G>A		intron	N/A	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.6655-24G>A		intron	N/A	ENSP00000593275.1
	SETX	ENST00000923217.1		c.6655-24G>A		intron	N/A	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67058 AN: 151646 Hom.: 17894 Cov.: 30

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.416

GnomAD2 exomes AF: 0.378 AC: 94805 AN: 251016 AF XY: 0.374

Gnomad AFR exome AF: 0.755

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.396

Gnomad EAS exome AF: 0.715

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.321 AC: 469136 AN: 1459342 Hom.: 84594 Cov.: 32 AF XY: 0.325 AC XY: 235758 AN XY: 726154

African (AFR) AF: 0.762 AC: 25490 AN: 33460

American (AMR) AF: 0.295 AC: 13185 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 10268 AN: 26116

East Asian (EAS) AF: 0.723 AC: 28701 AN: 39684

South Asian (SAS) AF: 0.436 AC: 37622 AN: 86202

European-Finnish (FIN) AF: 0.300 AC: 15997 AN: 53372

Middle Eastern (MID) AF: 0.507 AC: 2919 AN: 5756

European-Non Finnish (NFE) AF: 0.282 AC: 312581 AN: 1109746

Other (OTH) AF: 0.371 AC: 22373 AN: 60310

GnomAD4 genome AF: 0.443 AC: 67157 AN: 151764 Hom.: 17939 Cov.: 30 AF XY: 0.442 AC XY: 32783 AN XY: 74154

African (AFR) AF: 0.745 AC: 30850 AN: 41408

American (AMR) AF: 0.345 AC: 5246 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1413 AN: 3468

East Asian (EAS) AF: 0.698 AC: 3600 AN: 5154

South Asian (SAS) AF: 0.453 AC: 2179 AN: 4814

European-Finnish (FIN) AF: 0.292 AC: 3070 AN: 10496

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19609 AN: 67900

Other (OTH) AF: 0.415 AC: 874 AN: 2104

Alfa AF: 0.331 Hom.: 5184

Bravo AF: 0.462

Asia WGS AF: 0.565 AC: 1967 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	-	1	not specified (1)
-	-	1	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.052
DANN	Benign	0.75
PhyloP100		-0.88
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: rs11243704; hg19: chr9-135153668; COSMIC: COSV56380957; COSMIC: COSV56380957;