14-92071010-CCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG
• rs193922928
• NM_004993.6:c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_004993.6(ATXN3):​c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG​(p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln) 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 0.069 (524 hom., cov: 20)
  • Exomes 𝑓: 0.025 (221 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004993.6
• BP6: Variant 14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 1050021.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 10 of 11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 9883 AN: 142238 Hom.: 524 Cov.: 20

Gnomad AFR AF: 0.0488

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0660

Gnomad EAS AF: 0.00409

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.0723

Gnomad MID AF: 0.0230

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0680

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0249 AC: 32736 AN: 1312834 Hom.: 221 Cov.: 92 AF XY: 0.0263 AC XY: 17266 AN XY: 656116

African (AFR) AF: 0.0207 AC: 569 AN: 27524

American (AMR) AF: 0.0433 AC: 1751 AN: 40482

Ashkenazi Jewish (ASJ) AF: 0.0335 AC: 817 AN: 24384

East Asian (EAS) AF: 0.00192 AC: 72 AN: 37442

South Asian (SAS) AF: 0.0223 AC: 1773 AN: 79462

European-Finnish (FIN) AF: 0.0560 AC: 2734 AN: 48850

Middle Eastern (MID) AF: 0.0288 AC: 148 AN: 5136

European-Non Finnish (NFE) AF: 0.0230 AC: 22900 AN: 994524

Other (OTH) AF: 0.0358 AC: 1972 AN: 55030

GnomAD4 genome AF: 0.0695 AC: 9888 AN: 142348 Hom.: 524 Cov.: 20 AF XY: 0.0696 AC XY: 4814 AN XY: 69142

African (AFR) AF: 0.0488 AC: 1770 AN: 36280

American (AMR) AF: 0.102 AC: 1462 AN: 14384

Ashkenazi Jewish (ASJ) AF: 0.0660 AC: 225 AN: 3408

East Asian (EAS) AF: 0.00410 AC: 19 AN: 4634

South Asian (SAS) AF: 0.0353 AC: 152 AN: 4310

European-Finnish (FIN) AF: 0.0723 AC: 713 AN: 9862

Middle Eastern (MID) AF: 0.0177 AC: 5 AN: 282

European-Non Finnish (NFE) AF: 0.0801 AC: 5315 AN: 66346

Other (OTH) AF: 0.0678 AC: 133 AN: 1962

Alfa AF: 0.0280 Hom.: 345

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

- -

not provided Benign:1

-

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_Gly23ins13 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 13 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. -

Computational scores

Source: dbNSFP v4.3

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: COSV61495655; COSMIC: COSV61495655;