chr3-63912684-G-GGCAGCA

Variant names:

• chr3-63912684-G-GGCAGCA
• rs193922929
• NM_001377405.1:c.113_118dupAGCAGC

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_001377405.1(ATXN7):​c.113_118dupAGCAGC​(p.Gln38_Gln39dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.106 in 1,086,078 control chromosomes in the GnomAD database, including 4,589 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.098 (776 hom., cov: 23)
  • Exomes 𝑓: 0.11 (3813 hom.)
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 4.10

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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BP6: Variant 3-63912684-G-GGCAGCA is Benign according to our data. Variant chr3-63912684-G-GGCAGCA is described in ClinVar as [Likely_benign]. Clinvar id is 402403.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.113_118dupAGCAGC	p.Gln38_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.113_118dupAGCAGC	p.Gln38_Gln39dup	disruptive_inframe_insertion	Exon 2 of 13		NP_001170858.1
ATXN7	NM_000333.4	c.113_118dupAGCAGC	p.Gln38_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13		NP_000324.1
ATXN7	NM_001377406.1	c.113_118dupAGCAGC	p.Gln38_Gln39dup	disruptive_inframe_insertion	Exon 2 of 12		NP_001364335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.113_118dupAGCAGC	p.Gln38_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14097 AN: 144536 Hom.: 777 Cov.: 23

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.0408

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.0492 AC: 510 AN: 10356 Hom.: 25 AF XY: 0.0484 AC XY: 268 AN XY: 5542

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0293

Gnomad ASJ exome AF: 0.0320

Gnomad EAS exome AF: 0.0294

Gnomad SAS exome AF: 0.0233

Gnomad FIN exome AF: 0.0459

Gnomad NFE exome AF: 0.0731

Gnomad OTH exome AF: 0.0350

GnomAD4 exome AF: 0.107 AC: 100873 AN: 941440 Hom.: 3813 Cov.: 26 AF XY: 0.108 AC XY: 48317 AN XY: 446124

Gnomad4 AFR exome AF: 0.0584

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0559

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.0975 AC: 14106 AN: 144638 Hom.: 776 Cov.: 23 AF XY: 0.0960 AC XY: 6756 AN XY: 70368

Gnomad4 AFR AF: 0.0618

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.0626

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.117

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinal dystrophy Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Poly-Q expansions in this gene associated with spinocerebellar ataxia 7. SCA7 is characterized by progressive cerebellar ataxia, including dysarthria and dysphagia, and cone-rod and retinal dystrophy with progressive central visual loss resulting in blindness in affected adults. Onset in early childhood or infancy has an especially rapid and aggressive course often associated with failure to thrive and regression of motor milestones. Affected individuals usually have greater than 36 CAG repeats, although individuals with fewer repeats may also present with symptoms. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922929; hg19: chr3-63898360;