3-63912684-G-GGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_001377405.1(ATXN7):c.104_118dup(p.Gln35_Gln39dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00144 in 144,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00083 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN7 NM_001377405.1 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter 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 -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BP6: Variant 3-63912684-G-GGCAGCAGCAGCAGCA is Benign according to our data. Variant chr3-63912684-G-GGCAGCAGCAGCAGCA is described in ClinVar as [Benign]. Clinvar id is 2653939.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 208 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN7	NM_001377405.1	c.104_118dup	p.Gln35_Gln39dup	inframe_insertion	3/13	ENST00000674280.1
ATXN7	NM_000333.4	c.104_118dup	p.Gln35_Gln39dup	inframe_insertion	3/13
ATXN7	NM_001177387.1	c.104_118dup	p.Gln35_Gln39dup	inframe_insertion	2/13
ATXN7	NM_001377406.1	c.104_118dup	p.Gln35_Gln39dup	inframe_insertion	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN7	ENST00000674280.1	c.104_118dup	p.Gln35_Gln39dup	inframe_insertion	3/13		NM_001377405.1	P2

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 208 AN: 144616 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00293

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.00105

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.000235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00199

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000826 AC: 778 AN: 942100 Hom.: 4 Cov.: 26 AF XY: 0.000820 AC XY: 366 AN XY: 446440

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000238

Gnomad4 EAS exome AF: 0.00312

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.000424

Gnomad4 NFE exome AF: 0.000791

Gnomad4 OTH exome AF: 0.000937

GnomAD4 genome AF: 0.00144 AC: 209 AN: 144718 Hom.: 0 Cov.: 23 AF XY: 0.00139 AC XY: 98 AN XY: 70412

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00292

Gnomad4 ASJ AF: 0.000296

Gnomad4 EAS AF: 0.00105

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.000235

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00197

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

ATXN7: BS1, BS2 -

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;