3-63912684-G-GGCAGCAGCA

Position:

• chr3-63912684-G-GGCAGCAGCA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BS1_Supporting BS2

The NM_001377405.1(ATXN7):​c.110_118dupAGCAGCAGC​(p.Gln37_Gln39dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.046 in 1,086,962 control chromosomes in the GnomAD database, including 796 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.034 (92 hom., cov: 23)
  • Exomes 𝑓: 0.048 (704 hom.)
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided 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 Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0342 (4953/144692) while in subpopulation NFE AF= 0.0483 (3159/65426). AF 95% confidence interval is 0.0469. There are 92 homozygotes in gnomad4. There are 2376 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 4953 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.110_118dupAGCAGCAGC	p.Gln37_Gln39dup	disruptive_inframe_insertion	3/13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.110_118dupAGCAGCAGC	p.Gln37_Gln39dup	disruptive_inframe_insertion	2/13		NP_001170858.1
ATXN7	NM_000333.4	c.110_118dupAGCAGCAGC	p.Gln37_Gln39dup	disruptive_inframe_insertion	3/13		NP_000324.1
ATXN7	NM_001377406.1	c.110_118dupAGCAGCAGC	p.Gln37_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.110_118dupAGCAGCAGC	p.Gln37_Gln39dup	disruptive_inframe_insertion	3/13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 4952 AN: 144590 Hom.: 93 Cov.: 23

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0618

Gnomad AMR AF: 0.0341

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.00649

Gnomad SAS AF: 0.0227

Gnomad FIN AF: 0.0356

Gnomad MID AF: 0.0296

Gnomad NFE AF: 0.0483

Gnomad OTH AF: 0.0369

GnomAD3 exomes AF: 0.0215 AC: 223 AN: 10356 Hom.: 4 AF XY: 0.0226 AC XY: 125 AN XY: 5542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00698

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00681

Gnomad FIN exome AF: 0.0237

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0478 AC: 45017 AN: 942270 Hom.: 704 Cov.: 26 AF XY: 0.0474 AC XY: 21160 AN XY: 446526

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.0349

Gnomad4 ASJ exome AF: 0.0596

Gnomad4 EAS exome AF: 0.00655

Gnomad4 SAS exome AF: 0.0310

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0502

Gnomad4 OTH exome AF: 0.0410

GnomAD4 genome AF: 0.0342 AC: 4953 AN: 144692 Hom.: 92 Cov.: 23 AF XY: 0.0338 AC XY: 2376 AN XY: 70390

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.0340

Gnomad4 ASJ AF: 0.0528

Gnomad4 EAS AF: 0.00650

Gnomad4 SAS AF: 0.0236

Gnomad4 FIN AF: 0.0356

Gnomad4 NFE AF: 0.0483

Gnomad4 OTH AF: 0.0365

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign: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

- -

ATXN7-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;