rs180696871

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001377405.1(ATXN7):c.*14C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,613,846 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0057 ( 34 hom. )

Consequence

ATXN7
NM_001377405.1 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.46

Publications

10 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028598905).

BP6

Variant 3-63999481-C-A is Benign according to our data. Variant chr3-63999481-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 599471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 610 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN7	NM_001377405.1 link	c.*14C>A		3_prime_UTR_variant	Exon 13 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.*14C>A		3_prime_UTR_variant	Exon 13 of 13		NM_001377405.1	ENSP00000501377.1		O15265-1

Frequencies

GnomAD3 genomes

AF:

0.00401

AC:

610

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000918

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00660

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00397

AC:

987

AN:

248820

AF XY:

0.00398

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.000987

Gnomad ASJ exome

AF:

0.00438

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00534

Gnomad NFE exome

AF:

0.00606

Gnomad OTH exome

AF:

0.00330

GnomAD4 exome

AF:

0.00574

AC:

8390

AN:

1461588

Hom.:

Cov.:

AF XY:

0.00549

AC XY:

3995

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

33472

American (AMR)

AF:

0.00123

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00429

AC:

112

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00227

AC:

196

AN:

86170

European-Finnish (FIN)

AF:

0.00532

AC:

284

AN:

53410

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00668

AC:

7422

AN:

1111868

Other (OTH)

AF:

0.00450

AC:

272

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

431

862

1293

1724

2155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.00401

AC:

610

AN:

152258

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000915

AC:

AN:

41528

American (AMR)

AF:

0.00176

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00249

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00660

AC:

449

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00530

Hom.:

Bravo

AF:

0.00380

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00750

AC:

ExAC

AF:

0.00388

AC:

469

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00421

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 26, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

ATXN7-related disorder

Benign:1

Mar 18, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.48

T;.

M_CAP

Benign

0.0073

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-1.0

PhyloP100

1.5

PrimateAI

Benign

0.36

PROVEAN

Benign

0.40

N;.

REVEL

Benign

0.055

Sift

Uncertain

0.0060

D;.

Sift4G

Benign

0.37

T;.

Polyphen

0.0020

B;B

Vest4

0.20

MutPred

0.14

Loss of glycosylation at T916 (P = 0.0744);Loss of glycosylation at T916 (P = 0.0744);

MVP

0.18

ClinPred

0.023

GERP RS

3.3

gMVP

0.028

Mutation Taster

=99/1

polymorphism

(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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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