rs1053338

Variant names:

• chr3-63982224-A-G
• rs1053338
• NM_001377405.1:c.791A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1055 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13757 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.11
• Publications: 44 publications found

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: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377405.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	NM_001377405.1	MANE Select	c.791A>G	p.Lys264Arg	missense	Exon 7 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.791A>G	p.Lys264Arg	missense	Exon 6 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.791A>G	p.Lys264Arg	missense	Exon 7 of 13	NP_000324.1	O15265-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	ENST00000674280.1	MANE Select	c.791A>G	p.Lys264Arg	missense	Exon 7 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.791A>G	p.Lys264Arg	missense	Exon 7 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000484332.1	TSL:1	c.356A>G	p.Lys119Arg	missense	Exon 3 of 9	ENSP00000428277.1	O15265-3

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

GnomAD2 exomes AF: 0.137 AC: 34194 AN: 249424 AF XY: 0.137

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 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

African (AFR) AF: 0.0320 AC: 1071 AN: 33480

American (AMR) AF: 0.204 AC: 9111 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4267 AN: 26136

East Asian (EAS) AF: 0.138 AC: 5496 AN: 39700

South Asian (SAS) AF: 0.130 AC: 11184 AN: 86256

European-Finnish (FIN) AF: 0.0727 AC: 3883 AN: 53416

Middle Eastern (MID) AF: 0.146 AC: 843 AN: 5768

European-Non Finnish (NFE) AF: 0.138 AC: 153701 AN: 1111990

Other (OTH) AF: 0.133 AC: 8048 AN: 60396

GnomAD4 genome AF: 0.106 AC: 16079 AN: 152108 Hom.: 1055 Cov.: 32 AF XY: 0.104 AC XY: 7739 AN XY: 74352

African (AFR) AF: 0.0351 AC: 1459 AN: 41530

American (AMR) AF: 0.158 AC: 2417 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 594 AN: 3468

East Asian (EAS) AF: 0.146 AC: 748 AN: 5140

South Asian (SAS) AF: 0.124 AC: 599 AN: 4814

European-Finnish (FIN) AF: 0.0673 AC: 713 AN: 10598

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9196 AN: 67974

Other (OTH) AF: 0.132 AC: 279 AN: 2112

Alfa AF: 0.129 Hom.: 5555

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.038
Sift	Benign	0.091	T
Sift4G	Benign	0.22	T
Polyphen		0.60	P
Vest4		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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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