Genetic Variant NM_015046.7:c.5811T>C (chr9-132297025-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015046.7(SETX):c.5811T>C(p.Asp1937Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,012 control chromosomes in the GnomAD database, including 51,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 11023 hom., cov: 32)

Exomes 𝑓: 0.20 ( 40460 hom. )

Consequence

SETX
NM_015046.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.690

Publications

21 publications found

Variant links:

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

SETX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 9-132297025-A-G is Benign according to our data. Variant chr9-132297025-A-G is described in ClinVar as Benign. ClinVar VariationId is 95667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.69 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETX	NM_015046.7	MANE Select	c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 26	NP_055861.3
SETX	NM_001351528.2		c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 27	NP_001338457.1
SETX	NM_001351527.2		c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 26	NP_001338456.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETX	ENST00000224140.6	TSL:1 MANE Select	c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 26	ENSP00000224140.5
SETX	ENST00000923216.1		c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 28	ENSP00000593275.1
SETX	ENST00000923217.1		c.5811T>C	p.Asp1937Asp	synonymous	Exon 14 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes

AF:

0.317

AC:

48155

AN:

151882

Hom.:

10981

Cov.:

show subpopulations

Gnomad AFR

AF:

0.615

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.213

Gnomad ASJ

AF:

0.266

Gnomad EAS

AF:

0.671

Gnomad SAS

AF:

0.380

Gnomad FIN

AF:

0.169

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.274

GnomAD2 exomes

AF:

0.265

AC:

66348

AN:

249954

AF XY:

0.260

show subpopulations

Gnomad AFR exome

AF:

0.626

Gnomad AMR exome

AF:

0.205

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.689

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.199

AC:

290173

AN:

1460014

Hom.:

40460

Cov.:

AF XY:

0.202

AC XY:

147009

AN XY:

726382

show subpopulations

African (AFR)

AF:

0.632

AC:

21121

AN:

33432

American (AMR)

AF:

0.206

AC:

9210

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

6608

AN:

26104

East Asian (EAS)

AF:

0.706

AC:

28001

AN:

39668

South Asian (SAS)

AF:

0.362

AC:

31144

AN:

86146

European-Finnish (FIN)

AF:

0.169

AC:

8980

AN:

53292

Middle Eastern (MID)

AF:

0.342

AC:

1969

AN:

5764

European-Non Finnish (NFE)

AF:

0.152

AC:

168358

AN:

1110656

Other (OTH)

AF:

0.245

AC:

14782

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

9985

19971

29956

39942

49927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6604

13208

19812

26416

33020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.317

AC:

48251

AN:

151998

Hom.:

11023

Cov.:

AF XY:

0.320

AC XY:

23733

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.616

AC:

25524

AN:

41446

American (AMR)

AF:

0.214

AC:

3266

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.266

AC:

922

AN:

3472

East Asian (EAS)

AF:

0.670

AC:

3463

AN:

5166

South Asian (SAS)

AF:

0.380

AC:

1829

AN:

4818

European-Finnish (FIN)

AF:

0.169

AC:

1784

AN:

10562

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.157

AC:

10665

AN:

67952

Other (OTH)

AF:

0.275

AC:

580

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1360

2720

4079

5439

6799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.220

Hom.:

4987

Bravo

AF:

0.335

Asia WGS

AF:

0.503

AC:

1750

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

not provided (3)

Amyotrophic lateral sclerosis type 4 (2)

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)

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

-0.58

CADD

Benign

7.0

(source)

DANN

Benign

0.46

PhyloP100

0.69

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over