3-63912684-GGCAGCAGCAGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

• chr3-63912684-G-GGCAGCAGCAGCAGCAGCA
• rs193922929
• NM_001377405.1:c.101_118dupAGCAGCAGCAGCAGCAGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001377405.1(ATXN7):​c.101_118dupAGCAGCAGCAGCAGCAGC​(p.Gln34_Gln39dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000574 in 144,718 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00043 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.10
• Publications: 0 publications found

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]

ATXN7 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• spinocerebellar ataxia type 7

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BS2: High AC in GnomAd4 at 83 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377405.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	NM_001377405.1	MANE Select	c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	NP_000324.1	O15265-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	ENST00000674280.1	MANE Select	c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000522345.2	TSL:2	c.101_118dupAGCAGCAGCAGCAGCAGC	p.Gln34_Gln39dup	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes AF: 0.000574 AC: 83 AN: 144616 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000204

Gnomad ASJ AF: 0.000593

Gnomad EAS AF: 0.000209

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.000235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000336

Gnomad OTH AF: 0.000498

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000429 AC: 404 AN: 942366 Hom.: 2 Cov.: 26 AF XY: 0.000439 AC XY: 196 AN XY: 446554

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000847 AC: 15 AN: 17712

American (AMR) AF: 0.000379 AC: 2 AN: 5282

Ashkenazi Jewish (ASJ) AF: 0.000833 AC: 7 AN: 8400

East Asian (EAS) AF: 0.000728 AC: 7 AN: 9614

South Asian (SAS) AF: 0.000350 AC: 7 AN: 20022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18856

Middle Eastern (MID) AF: 0.00143 AC: 3 AN: 2096

European-Non Finnish (NFE) AF: 0.000423 AC: 350 AN: 827280

Other (OTH) AF: 0.000393 AC: 13 AN: 33104

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000574 AC: 83 AN: 144718 Hom.: 0 Cov.: 23 AF XY: 0.000483 AC XY: 34 AN XY: 70412

African (AFR) AF: 0.00128 AC: 51 AN: 39998

American (AMR) AF: 0.000204 AC: 3 AN: 14702

Ashkenazi Jewish (ASJ) AF: 0.000593 AC: 2 AN: 3374

East Asian (EAS) AF: 0.000210 AC: 1 AN: 4766

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4708

European-Finnish (FIN) AF: 0.000235 AC: 2 AN: 8512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000336 AC: 22 AN: 65440

Other (OTH) AF: 0.000493 AC: 1 AN: 2030

Alfa AF: 0.000286 Hom.: 39

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=68/32	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922929; hg19: chr3-63898360;