3-63912714-A-AGCAGCC

Variant summary

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

The NM_001377405.1(ATXN7):c.118_119insAGCCGC(p.Gln39_Pro40insGlnPro) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,212,244 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: ATXN7 NM_001377405.1 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.825

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 3-63912714-A-AGCAGCC is Benign according to our data. Variant chr3-63912714-A-AGCAGCC is described in ClinVar as [Likely_benign]. Clinvar id is 2653940.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 442 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN7	NM_001377405.1	c.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	inframe_insertion	3/13	ENST00000674280.1
ATXN7	NM_000333.4	c.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	inframe_insertion	3/13
ATXN7	NM_001177387.1	c.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	inframe_insertion	2/13
ATXN7	NM_001377406.1	c.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	inframe_insertion	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN7	ENST00000674280.1	c.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	inframe_insertion	3/13		NM_001377405.1	P2

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 442 AN: 146890 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00148

Gnomad ASJ AF: 0.00413

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.000547

Gnomad MID AF: 0.0258

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00247

GnomAD3 exomes AF: 0.000125 AC: 4 AN: 32074 Hom.: 0 AF XY: 0.0000552 AC XY: 1 AN XY: 18122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00195 AC: 2075 AN: 1065246 Hom.: 2 Cov.: 32 AF XY: 0.00193 AC XY: 984 AN XY: 510420

Gnomad4 AFR exome AF: 0.00497

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00181

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000270

Gnomad4 FIN exome AF: 0.000158

Gnomad4 NFE exome AF: 0.00204

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00301 AC: 443 AN: 146998 Hom.: 1 Cov.: 31 AF XY: 0.00295 AC XY: 211 AN XY: 71544

Gnomad4 AFR AF: 0.00576

Gnomad4 AMR AF: 0.00148

Gnomad4 ASJ AF: 0.00413

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000630

Gnomad4 FIN AF: 0.000547

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.00244

Alfa AF: 0.000374 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

ATXN7: BS1 -

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: rs770364745; hg19: chr3-63898390;