3-63912684-GGCAGCAGCAGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Position:

• chr3-63912684-GGCAGCAGCAGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001377405.1(ATXN7):​c.101_118dupAGCAGCAGCAGCAGCAGC​(p.Gln34_Gln39dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000574 in 144,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00043 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U: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 Likely_benign. Variant got -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BS2: High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	3/13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	2/13		NP_001170858.1
ATXN7	NM_000333.4	c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	3/13		NP_000324.1
ATXN7	NM_001377406.1	c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	2/12		NP_001364335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	3/13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.000574 AC: 83 AN: 144616 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000204

Gnomad ASJ AF: 0.000593

Gnomad EAS AF: 0.000209

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.000235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000336

Gnomad OTH AF: 0.000498

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000429 AC: 404 AN: 942366 Hom.: 2 Cov.: 26 AF XY: 0.000439 AC XY: 196 AN XY: 446554

Gnomad4 AFR exome AF: 0.000847

Gnomad4 AMR exome AF: 0.000379

Gnomad4 ASJ exome AF: 0.000833

Gnomad4 EAS exome AF: 0.000728

Gnomad4 SAS exome AF: 0.000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000423

Gnomad4 OTH exome AF: 0.000393

GnomAD4 genome AF: 0.000574 AC: 83 AN: 144718 Hom.: 0 Cov.: 23 AF XY: 0.000483 AC XY: 34 AN XY: 70412

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000204

Gnomad4 ASJ AF: 0.000593

Gnomad4 EAS AF: 0.000210

Gnomad4 SAS AF: 0.000212

Gnomad4 FIN AF: 0.000235

Gnomad4 NFE AF: 0.000336

Gnomad4 OTH AF: 0.000493

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

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

Jan 01, 2022

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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;