rs1053338

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001377405.1(ATXN7):c.791A>G(p.Lys264Arg) variant causes a missense change. The variant allele was found at a frequency of 0.132 in 1,613,974 control chromosomes in the GnomAD database, including 14,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.11 ( 1055 hom., cov: 32)

Exomes 𝑓: 0.14 ( 13757 hom. )

Consequence

ATXN7
NM_001377405.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.11

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015056431).

BP6

Variant 3-63982224-A-G is Benign according to our data. Variant chr3-63982224-A-G is described in ClinVar as [Benign]. Clinvar id is 128519.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN7	NM_001377405.1 link	c.791A>G	p.Lys264Arg	missense_variant	Exon 7 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.791A>G	p.Lys264Arg	missense_variant	Exon 7 of 13		NM_001377405.1	ENSP00000501377.1		O15265-1

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16077

AN:

151992

Hom.:

1054

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0352

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.0673

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.133

GnomAD3 exomes

AF:

0.137

AC:

34194

AN:

249424

Hom.:

2613

AF XY:

0.137

AC XY:

18585

AN XY:

135332

show subpopulations

Gnomad AFR exome

AF:

0.0349

Gnomad AMR exome

AF:

0.209

Gnomad ASJ exome

AF:

0.165

Gnomad EAS exome

AF:

0.156

Gnomad SAS exome

AF:

0.129

Gnomad FIN exome

AF:

0.0691

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.135

AC:

197604

AN:

1461866

Hom.:

13757

Cov.:

AF XY:

0.135

AC XY:

98208

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0320

Gnomad4 AMR exome

AF:

0.204

Gnomad4 ASJ exome

AF:

0.163

Gnomad4 EAS exome

AF:

0.138

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.0727

Gnomad4 NFE exome

AF:

0.138

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.106

AC:

16079

AN:

152108

Hom.:

1055

Cov.:

AF XY:

0.104

AC XY:

7739

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0351

Gnomad4 AMR

AF:

0.158

Gnomad4 ASJ

AF:

0.171

Gnomad4 EAS

AF:

0.146

Gnomad4 SAS

AF:

0.124

Gnomad4 FIN

AF:

0.0673

Gnomad4 NFE

AF:

0.135

Gnomad4 OTH

AF:

0.132

Alfa

AF:

0.132

Hom.:

2764

Bravo

AF:

0.113

TwinsUK

AF:

0.128

AC:

476

ALSPAC

AF:

0.132

AC:

507

ESP6500AA

AF:

0.0351

AC:

140

ESP6500EA

AF:

0.131

AC:

1091

ExAC

AF:

0.134

AC:

16231

Asia WGS

AF:

0.106

AC:

370

AN:

3478

EpiCase

AF:

0.132

EpiControl

AF:

0.141

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

0.071

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

.;T;.;T;.;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

T;T;T;.;.;T

MetaRNN

Benign

0.0015

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;L;L;L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

.;N;N;N;.;N

REVEL

Benign

0.038

Sift

Benign

0.091

.;T;T;T;.;T

Sift4G

Benign

0.22

.;T;T;T;.;T

Polyphen

0.60, 0.72

.;P;P;P;P;.

Vest4

0.16, 0.23, 0.17, 0.16

ClinPred

0.024

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.086

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over