9-132275229-T-C

Variant names:

• chr9-132275229-T-C
• rs2296865
• NM_015046.7:c.7100+27A>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+27A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,607,116 control chromosomes in the GnomAD database, including 19,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2655 hom., cov: 32)
  • Exomes 𝑓: 0.13 (17234 hom.)
• Consequence: SETX NM_015046.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.583
• 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=-0.88).
• BP6: Variant 9-132275229-T-C is Benign according to our data. Variant chr9-132275229-T-C is described in ClinVar as Benign. ClinVar VariationId is 260516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7	c.7100+27A>G		intron_variant	Intron 23 of 25	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.7100+27A>G		intron_variant	Intron 23 of 25	1	NM_015046.7	ENSP00000224140.5
SETX	ENST00000464133.1	n.325A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
SETX	ENST00000436441.5	c.1826+27A>G		intron_variant	Intron 13 of 16	5		ENSP00000409143.1
SETX	ENST00000477049.1	n.127+27A>G		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25615 AN: 151998 Hom.: 2654 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.171 AC: 42922 AN: 250898 AF XY: 0.173

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.134 AC: 195373 AN: 1455000 Hom.: 17234 Cov.: 29 AF XY: 0.138 AC XY: 100111 AN XY: 724314

African (AFR) AF: 0.254 AC: 8447 AN: 33310

American (AMR) AF: 0.143 AC: 6402 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4874 AN: 26052

East Asian (EAS) AF: 0.457 AC: 18115 AN: 39614

South Asian (SAS) AF: 0.266 AC: 22855 AN: 86062

European-Finnish (FIN) AF: 0.119 AC: 6326 AN: 53020

Middle Eastern (MID) AF: 0.265 AC: 1522 AN: 5746

European-Non Finnish (NFE) AF: 0.106 AC: 117001 AN: 1106390

Other (OTH) AF: 0.164 AC: 9831 AN: 60100

GnomAD4 genome AF: 0.169 AC: 25643 AN: 152116 Hom.: 2655 Cov.: 32 AF XY: 0.173 AC XY: 12850 AN XY: 74356

African (AFR) AF: 0.243 AC: 10065 AN: 41480

American (AMR) AF: 0.141 AC: 2153 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 711 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2207 AN: 5164

South Asian (SAS) AF: 0.282 AC: 1357 AN: 4806

European-Finnish (FIN) AF: 0.116 AC: 1226 AN: 10596

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

European-Non Finnish (NFE) AF: 0.109 AC: 7424 AN: 68000

Other (OTH) AF: 0.164 AC: 347 AN: 2114

Alfa AF: 0.132 Hom.: 650

Bravo AF: 0.174

Asia WGS AF: 0.348 AC: 1208 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 4 Benign:1

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Benign:1

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.59
PhyloP100		-0.58
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: rs2296865; hg19: chr9-135150616; COSMIC: COSV56391825;