3-63912684-G-GGCAGCAGCA
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3BS1_SupportingBS2
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
NM_001377405.1 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATXN7 | NM_001377405.1 | c.110_118dupAGCAGCAGC | p.Gln37_Gln39dup | disruptive_inframe_insertion | Exon 3 of 13 | ENST00000674280.1 | NP_001364334.1 | |
| ATXN7 | NM_001177387.1 | c.110_118dupAGCAGCAGC | p.Gln37_Gln39dup | disruptive_inframe_insertion | Exon 2 of 13 | NP_001170858.1 | ||
| ATXN7 | NM_000333.4 | c.110_118dupAGCAGCAGC | p.Gln37_Gln39dup | disruptive_inframe_insertion | Exon 3 of 13 | NP_000324.1 | ||
| ATXN7 | NM_001377406.1 | c.110_118dupAGCAGCAGC | p.Gln37_Gln39dup | disruptive_inframe_insertion | Exon 2 of 12 | NP_001364335.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0342 AC: 4952AN: 144590Hom.: 93 Cov.: 23
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GnomAD3 exomes AF: 0.0215 AC: 223AN: 10356Hom.: 4 AF XY: 0.0226 AC XY: 125AN XY: 5542
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GnomAD4 exome AF: 0.0478 AC: 45017AN: 942270Hom.: 704 Cov.: 26 AF XY: 0.0474 AC XY: 21160AN XY: 446526
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GnomAD4 genome 0.0342 AC: 4953AN: 144692Hom.: 92 Cov.: 23 AF XY: 0.0338 AC XY: 2376AN XY: 70390
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: no assertion criteria provided
LINK: link
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
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ATXN7-related disorder Benign:1
Jul 03, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at