NM_015046.7:c.6546+32T>A

Variant names:

• chr9-132283232-A-T
• rs2296873
• NM_015046.7:c.6546+32T>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.6546+32T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0508 in 1,613,742 control chromosomes in the GnomAD database, including 5,918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (833 hom., cov: 32)
  • Exomes 𝑓: 0.048 (5085 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.263
• 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: 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=-0.71).
• BP6: Variant 9-132283232-A-T is Benign according to our data. Variant chr9-132283232-A-T is described in ClinVar as Benign. ClinVar VariationId is 260512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 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.6546+32T>A		intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.6546+32T>A		intron	N/A	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.6546+32T>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.6546+32T>A		intron	N/A	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.6546+32T>A		intron	N/A	ENSP00000593275.1
	SETX	ENST00000923217.1		c.6546+32T>A		intron	N/A	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.0755 AC: 11475 AN: 152066 Hom.: 831 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0697

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0469

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0276

Gnomad OTH AF: 0.0664

GnomAD2 exomes AF: 0.0830 AC: 20863 AN: 251328 AF XY: 0.0794

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0995

Gnomad ASJ exome AF: 0.0486

Gnomad EAS exome AF: 0.391

Gnomad FIN exome AF: 0.0447

Gnomad NFE exome AF: 0.0273

Gnomad OTH exome AF: 0.0616

GnomAD4 exome AF: 0.0483 AC: 70554 AN: 1461560 Hom.: 5085 Cov.: 32 AF XY: 0.0492 AC XY: 35765 AN XY: 727092

African (AFR) AF: 0.129 AC: 4326 AN: 33464

American (AMR) AF: 0.0975 AC: 4360 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0488 AC: 1276 AN: 26132

East Asian (EAS) AF: 0.406 AC: 16131 AN: 39684

South Asian (SAS) AF: 0.104 AC: 8991 AN: 86244

European-Finnish (FIN) AF: 0.0450 AC: 2406 AN: 53416

Middle Eastern (MID) AF: 0.0779 AC: 449 AN: 5766

European-Non Finnish (NFE) AF: 0.0256 AC: 28406 AN: 1111758

Other (OTH) AF: 0.0697 AC: 4209 AN: 60376

GnomAD4 genome AF: 0.0755 AC: 11494 AN: 152182 Hom.: 833 Cov.: 32 AF XY: 0.0791 AC XY: 5887 AN XY: 74400

African (AFR) AF: 0.123 AC: 5086 AN: 41518

American (AMR) AF: 0.0704 AC: 1077 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3470

East Asian (EAS) AF: 0.379 AC: 1959 AN: 5170

South Asian (SAS) AF: 0.127 AC: 610 AN: 4822

European-Finnish (FIN) AF: 0.0469 AC: 496 AN: 10582

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0276 AC: 1880 AN: 68010

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0248 Hom.: 27

Bravo AF: 0.0816

Asia WGS AF: 0.255 AC: 885 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	-0.71
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2296873; hg19: chr9-135158619;