NM_015046.7:c.6935+8T>C

Variant names:

• chr9-132277052-A-G
• rs17148873
• NM_015046.7:c.6935+8T>C

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.6935+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0867 in 1,609,646 control chromosomes in the GnomAD database, including 6,849 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (759 hom., cov: 32)
  • Exomes 𝑓: 0.086 (6090 hom.)
• Consequence: SETX NM_015046.7 splice_region, intron
• Scores: Splicing: ADA: 0.0001784
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.447
• Publications: 9 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=-0.8).
• BP6: Variant 9-132277052-A-G is Benign according to our data. Variant chr9-132277052-A-G is described in ClinVar as Benign. ClinVar VariationId is 260514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.146 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.6935+8T>C		splice_region intron	N/A	NP_055861.3
	SETX	NM_001351528.2		c.6935+8T>C		splice_region intron	N/A	NP_001338457.1
	SETX	NM_001351527.2		c.6935+8T>C		splice_region 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.6935+8T>C		splice_region intron	N/A	ENSP00000224140.5
	SETX	ENST00000436441.5	TSL:5	c.1661+8T>C		splice_region intron	N/A	ENSP00000409143.1
	SETX	ENST00000464133.1	TSL:2	n.133+8T>C		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0944 AC: 14362 AN: 152154 Hom.: 757 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0498

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0818

Gnomad OTH AF: 0.0960

GnomAD2 exomes AF: 0.0883 AC: 22174 AN: 251174 AF XY: 0.0934

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.0426

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.0429

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0846

Gnomad OTH exome AF: 0.0932

GnomAD4 exome AF: 0.0859 AC: 125233 AN: 1457376 Hom.: 6090 Cov.: 30 AF XY: 0.0889 AC XY: 64444 AN XY: 725290

African (AFR) AF: 0.128 AC: 4285 AN: 33378

American (AMR) AF: 0.0456 AC: 2041 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3620 AN: 26100

East Asian (EAS) AF: 0.0532 AC: 2109 AN: 39676

South Asian (SAS) AF: 0.160 AC: 13758 AN: 86146

European-Finnish (FIN) AF: 0.0740 AC: 3945 AN: 53308

Middle Eastern (MID) AF: 0.184 AC: 1059 AN: 5760

European-Non Finnish (NFE) AF: 0.0801 AC: 88781 AN: 1108046

Other (OTH) AF: 0.0935 AC: 5635 AN: 60238

GnomAD4 genome AF: 0.0944 AC: 14375 AN: 152270 Hom.: 759 Cov.: 32 AF XY: 0.0948 AC XY: 7062 AN XY: 74458

African (AFR) AF: 0.125 AC: 5186 AN: 41532

American (AMR) AF: 0.0699 AC: 1070 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 532 AN: 3472

East Asian (EAS) AF: 0.0499 AC: 259 AN: 5188

South Asian (SAS) AF: 0.155 AC: 749 AN: 4830

European-Finnish (FIN) AF: 0.0682 AC: 723 AN: 10602

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0818 AC: 5563 AN: 68026

Other (OTH) AF: 0.0945 AC: 200 AN: 2116

Alfa AF: 0.0876 Hom.: 2756

Bravo AF: 0.0940

Asia WGS AF: 0.0940 AC: 328 AN: 3478

EpiCase AF: 0.0849

EpiControl AF: 0.0900

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	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	-0.80
CADD	Benign	7.7
DANN	Benign	0.78
PhyloP100		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.014
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: rs17148873; hg19: chr9-135152439; COSMIC: COSV56392383; COSMIC: COSV56392383;