NM_004993.6:c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTG
• rs193922928
• NM_004993.6:c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_004993.6(ATXN3):​c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG​(p.Gln297_Gln305dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5355 hom., cov: 20)
  • Exomes 𝑓: 0.27 (38089 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.168
• Publications: 1 publications found

Genes affected

ATXN3 (HGNC:7106): (ataxin 3) Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2016]

ATXN3 Gene-Disease associations (from GenCC):

• Machado-Joseph disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Machado-Joseph disease type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000303901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004993.6
• BP6: Variant 14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 1050334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004993.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	NM_004993.6	MANE Select	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln297_Gln305dup	conservative_inframe_insertion	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.870_871insCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln282_Gln290dup	conservative_inframe_insertion	Exon 9 of 10	NP_001121168.1
	ATXN3	NM_001127697.3		c.762_763insCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln246_Gln254dup	conservative_inframe_insertion	Exon 8 of 9	NP_001121169.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln297_Gln305dup	conservative_inframe_insertion	Exon 10 of 11	ENSP00000496695.1
	ATXN3	ENST00000532032.5	TSL:1	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln297_Gln305dup	conservative_inframe_insertion	Exon 10 of 10	ENSP00000437157.1
	ATXN3	ENST00000503767.5	TSL:1	c.870_871insCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln282_Gln290dup	conservative_inframe_insertion	Exon 9 of 10	ENSP00000426697.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 35384 AN: 142178 Hom.: 5352 Cov.: 20

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.277

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.272 AC: 343134 AN: 1261568 Hom.: 38089 Cov.: 92 AF XY: 0.269 AC XY: 169994 AN XY: 631004

African (AFR) AF: 0.102 AC: 2780 AN: 27180

American (AMR) AF: 0.338 AC: 13384 AN: 39624

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 6394 AN: 23460

East Asian (EAS) AF: 0.00910 AC: 340 AN: 37374

South Asian (SAS) AF: 0.254 AC: 19554 AN: 77064

European-Finnish (FIN) AF: 0.227 AC: 10989 AN: 48392

Middle Eastern (MID) AF: 0.304 AC: 1524 AN: 5014

European-Non Finnish (NFE) AF: 0.289 AC: 274608 AN: 950128

Other (OTH) AF: 0.254 AC: 13561 AN: 53332

GnomAD4 genome AF: 0.249 AC: 35403 AN: 142284 Hom.: 5355 Cov.: 20 AF XY: 0.250 AC XY: 17288 AN XY: 69096

African (AFR) AF: 0.106 AC: 3832 AN: 36286

American (AMR) AF: 0.380 AC: 5463 AN: 14388

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1035 AN: 3410

East Asian (EAS) AF: 0.0166 AC: 77 AN: 4634

South Asian (SAS) AF: 0.284 AC: 1220 AN: 4294

European-Finnish (FIN) AF: 0.263 AC: 2587 AN: 9846

Middle Eastern (MID) AF: 0.316 AC: 89 AN: 282

European-Non Finnish (NFE) AF: 0.307 AC: 20384 AN: 66308

Other (OTH) AF: 0.281 AC: 551 AN: 1958

Alfa AF: 0.137 Hom.: 345

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATXN3 p.Ala22_Gly23ins9 variant was identified in dbSNP (ID: rs763541221), ClinVar, Cosmic and LOVD 3.0. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame insertion resulting in the inclusion of nine CAG repeats. The (CAG)n repeat within the ATXN3 gene was found to cause Machado-Joseph disease at 73-78 repeats while 14-40 repeats was considered the normal range (Limprasert_1996_PMID: 8824876). More recent studies have suggested 52 to 86 repeats as pathogenic (GeneReviews). This CAG repeat expansion would fall within the normal range and this variant is predicted to be a polymorphism by MutationTaster. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Nov 27, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=80/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs193922928; hg19: chr14-92537354; COSMIC: COSV61493678; COSMIC: COSV61493678;