rs1053338

Positions:

• chr3-63982224-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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 Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1055 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13757 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.11

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]

ACMG classification

Verdict is Benign. Variant got -13 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 [Likely_benign]. Clinvar id is 128519.Status of the report is no_assertion_criteria_provided, 0 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/exons	MANE	UniProt
ATXN7	NM_001377405.1	c.791A>G	p.Lys264Arg	missense_variant	7/13	ENST00000674280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN7	ENST00000674280.1	c.791A>G	p.Lys264Arg	missense_variant	7/13		NM_001377405.1	P2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16077 AN: 151992 Hom.: 1054 Cov.: 32

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

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.: 33 AF XY: 0.135 AC XY: 98208 AN XY: 727234

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.: 32 AF XY: 0.104 AC XY: 7739 AN XY: 74352

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: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T;T;T;.;.;T
MetaRNN	Benign	0.0015	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.00031	P;P;P;P;P
PrimateAI	Benign	0.40	T
Polyphen		0.60, 0.72	.;P;P;P;P;.
Vest4		0.16, 0.23, 0.17, 0.16
ClinPred		0.024	T
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

Other links and lift over

dbSNP: rs1053338; hg19: chr3-63967900; COSMIC: COSV55753991; COSMIC: COSV55753991;