rs3774729

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001377405.1(ATXN7):c.2584G>A(p.Val862Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,796 control chromosomes in the GnomAD database, including 91,264 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.40 ( 13143 hom., cov: 31)

Exomes 𝑓: 0.32 ( 78121 hom. )

Consequence

ATXN7
NM_001377405.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.264

Publications

43 publications found

Variant links:

Genes affected

ATXN7 (HGNC:10560): (ataxin 7) The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the 'pure' cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. This locus has been mapped to chromosome 3, and it has been determined that the diseased allele associated with spinocerebellar ataxia-7 contains 37-306 CAG repeats (near the N-terminus), compared to 4-35 in the normal allele. The encoded protein is a component of the SPT3/TAF9/GCN5 acetyltransferase (STAGA) and TBP-free TAF-containing (TFTC) chromatin remodeling complexes, and it thus plays a role in transcriptional regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

ATXN7 Gene-Disease associations (from GenCC):

spinocerebellar ataxia 7
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
spinocerebellar ataxia type 7
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ATXN7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.7316197E-5).

BP6

Variant 3-63996406-G-A is Benign according to our data. Variant chr3-63996406-G-A is described in ClinVar as [Benign]. Clinvar id is 128518.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN7	NM_001377405.1 link	c.2584G>A	p.Val862Met	missense_variant	Exon 12 of 13	ENST00000674280.1	NP_001364334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1 link	c.2584G>A	p.Val862Met	missense_variant	Exon 12 of 13		NM_001377405.1	ENSP00000501377.1		O15265-1

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60465

AN:

151806

Hom.:

13114

Cov.:

show subpopulations

Gnomad AFR

AF:

0.578

Gnomad AMI

AF:

0.359

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.412

Gnomad EAS

AF:

0.481

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.324

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.317

Gnomad OTH

AF:

0.404

GnomAD2 exomes

AF:

0.344

AC:

85844

AN:

249242

AF XY:

0.339

show subpopulations

Gnomad AFR exome

AF:

0.584

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.401

Gnomad EAS exome

AF:

0.495

Gnomad FIN exome

AF:

0.315

Gnomad NFE exome

AF:

0.315

Gnomad OTH exome

AF:

0.342

GnomAD4 exome

AF:

0.322

AC:

470748

AN:

1461872

Hom.:

78121

Cov.:

AF XY:

0.321

AC XY:

233722

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.587

AC:

19664

AN:

33480

American (AMR)

AF:

0.301

AC:

13482

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

10427

AN:

26136

East Asian (EAS)

AF:

0.478

AC:

18971

AN:

39700

South Asian (SAS)

AF:

0.298

AC:

25715

AN:

86258

European-Finnish (FIN)

AF:

0.322

AC:

17225

AN:

53418

Middle Eastern (MID)

AF:

0.337

AC:

1945

AN:

5768

European-Non Finnish (NFE)

AF:

0.308

AC:

342115

AN:

1111992

Other (OTH)

AF:

0.351

AC:

21204

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

21649

43299

64948

86598

108247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.399

AC:

60542

AN:

151924

Hom.:

13143

Cov.:

AF XY:

0.396

AC XY:

29409

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.578

AC:

23944

AN:

41404

American (AMR)

AF:

0.332

AC:

5065

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.412

AC:

1429

AN:

3470

East Asian (EAS)

AF:

0.481

AC:

2467

AN:

5126

South Asian (SAS)

AF:

0.289

AC:

1396

AN:

4834

European-Finnish (FIN)

AF:

0.324

AC:

3425

AN:

10564

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.317

AC:

21523

AN:

67948

Other (OTH)

AF:

0.404

AC:

853

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1774

3549

5323

7098

8872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.343

Hom.:

36826

Bravo

AF:

0.409

TwinsUK

AF:

0.294

AC:

1089

ALSPAC

AF:

0.309

AC:

1190

ESP6500AA

AF:

0.558

AC:

2374

ESP6500EA

AF:

0.307

AC:

2612

ExAC

AF:

0.347

AC:

42058

Asia WGS

AF:

0.422

AC:

1468

AN:

3478

EpiCase

AF:

0.311

EpiControl

AF:

0.312

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

3.5

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.086

.;T;.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.51

T;T;T;.;.;T

MetaRNN

Benign

0.000037

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.79

.;N;N;N;N;.

PhyloP100

-0.26

PrimateAI

Benign

0.34

PROVEAN

Benign

0.45

.;N;N;N;.;N

REVEL

Benign

0.074

Sift

Benign

1.0

.;T;T;T;.;T

Sift4G

Benign

0.81

.;T;T;T;.;T

Polyphen

0.0050, 0.028

.;B;B;B;B;.

Vest4

0.032, 0.035, 0.071

ClinPred

0.0012

GERP RS

-1.6

Varity_R

0.017

gMVP

0.057

Mutation Taster

=100/0

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

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rs3774729

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over