NM_004993.6:c.916_917insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC

Variant names:

• chr14-92071009-C-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT
• rs763461489
• NM_004993.6:c.916_917insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_004993.6(ATXN3):​c.916_917insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC​(p.Gly306delinsGluGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnArg) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G306G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ATXN3 NM_004993.6 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.802
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004993.6.

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.916_917insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gly306delinsGluGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnArg	conservative_inframe_insertion	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.871_872insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gly291delinsGluGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnArg	conservative_inframe_insertion	Exon 9 of 10	NP_001121168.1
	ATXN3	NM_001127697.3		c.763_764insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gly255delinsGluGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnArg	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.916_917insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gly306delinsGluGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnArg	conservative_inframe_insertion	Exon 10 of 11	ENSP00000496695.1
	ATXN3	ENST00000532032.5	TSL:1	c.916_917insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gly306delinsGluGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnArg	conservative_inframe_insertion	Exon 10 of 10	ENSP00000437157.1
	ATXN3	ENST00000503767.5	TSL:1	c.871_872insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gly291delinsGluGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnArg	conservative_inframe_insertion	Exon 9 of 10	ENSP00000426697.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.80

Splicing

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

Other links and lift over

dbSNP: rs763461489; hg19: chr14-92537353; COSMIC: COSV107428781; COSMIC: COSV107428781;