3-63912714-A-AGCC

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_001377405.1(ATXN7):c.123_125dup(p.Pro42dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,212,028 control chromosomes in the GnomAD database, including 39 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (31 hom.)
• Consequence: ATXN7 NM_001377405.1 inframe_insertion
• Clinical Significance: 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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BP6: Variant 3-63912714-A-AGCC is Benign according to our data. Variant chr3-63912714-A-AGCC is described in ClinVar as [Benign]. Clinvar id is 2653941.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00737 (7854/1065024) while in subpopulation MID AF= 0.0273 (74/2712). AF 95% confidence interval is 0.0223. There are 31 homozygotes in gnomad4_exome. There are 3811 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1162 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN7	NM_001377405.1	c.123_125dup	p.Pro42dup	inframe_insertion	3/13	ENST00000674280.1
ATXN7	NM_000333.4	c.123_125dup	p.Pro42dup	inframe_insertion	3/13
ATXN7	NM_001177387.1	c.123_125dup	p.Pro42dup	inframe_insertion	2/13
ATXN7	NM_001377406.1	c.123_125dup	p.Pro42dup	inframe_insertion	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN7	ENST00000674280.1	c.123_125dup	p.Pro42dup	inframe_insertion	3/13		NM_001377405.1	P2

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1162 AN: 146896 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00216

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.00914

Gnomad EAS AF: 0.000415

Gnomad SAS AF: 0.00609

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.0323

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0133

GnomAD3 exomes AF: 0.00571 AC: 183 AN: 32074 Hom.: 1 AF XY: 0.00635 AC XY: 115 AN XY: 18122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00589

Gnomad ASJ exome AF: 0.00568

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00731

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00857

Gnomad OTH exome AF: 0.00954

GnomAD4 exome AF: 0.00737 AC: 7854 AN: 1065024 Hom.: 31 Cov.: 32 AF XY: 0.00747 AC XY: 3811 AN XY: 510288

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.00913

Gnomad4 EAS exome AF: 0.000810

Gnomad4 SAS exome AF: 0.00690

Gnomad4 FIN exome AF: 0.00313

Gnomad4 NFE exome AF: 0.00773

Gnomad4 OTH exome AF: 0.00790

GnomAD4 genome AF: 0.00792 AC: 1164 AN: 147004 Hom.: 8 Cov.: 31 AF XY: 0.00794 AC XY: 568 AN XY: 71544

Gnomad4 AFR AF: 0.00215

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.00914

Gnomad4 EAS AF: 0.000624

Gnomad4 SAS AF: 0.00630

Gnomad4 FIN AF: 0.00263

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00464 Hom.: 1

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, 2023

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: rs1553686135; hg19: chr3-63898390;