rs370363342

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_015046.7(SETX):c.1343A>G(p.Asp448Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,578,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D448A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.31

Publications

2 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: 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)

SETX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052416384).

BP6

Variant 9-132330255-T-C is Benign according to our data. Variant chr9-132330255-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 573505.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000854 (13/152242) while in subpopulation AMR AF = 0.00085 (13/15288). AF 95% confidence interval is 0.000503. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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	UniProt
SETX	NM_015046.7	MANE Select	c.1343A>G	p.Asp448Gly	missense	Exon 10 of 26	NP_055861.3
SETX	NM_001351528.2		c.1343A>G	p.Asp448Gly	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
SETX	NM_001351527.2		c.1343A>G	p.Asp448Gly	missense	Exon 10 of 26	NP_001338456.1	Q7Z333-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETX	ENST00000224140.6	TSL:1 MANE Select	c.1343A>G	p.Asp448Gly	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
SETX	ENST00000923216.1		c.1343A>G	p.Asp448Gly	missense	Exon 10 of 28	ENSP00000593275.1
SETX	ENST00000923217.1		c.1343A>G	p.Asp448Gly	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000146

AC:

AN:

226214

AF XY:

0.000115

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000992

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000186

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1426534

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

705352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32428

American (AMR)

AF:

0.000828

AC:

AN:

41060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23768

East Asian (EAS)

AF:

0.0000509

AC:

AN:

39320

South Asian (SAS)

AF:

0.00

AC:

AN:

80174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1093444

Other (OTH)

AF:

0.0000511

AC:

AN:

58726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000854

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.000850

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000245

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000124

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

SETX-related disorder (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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.55

PhyloP100

2.3

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.31

Sift

Uncertain

0.014

Sift4G

Uncertain

0.032

Polyphen

0.15

Vest4

0.39

MVP

0.74

MPC

0.18

ClinPred

0.038

GERP RS

1.9

Varity_R

0.088

gMVP

0.23

Mutation Taster

=17/83

disease causing

(source)

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

Publications

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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