NM_004993.6:c.916_917insA

Variant names:

• chr14-92071009-C-CT
• rs763461489
• NM_004993.6:c.916_917insA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004993.6(ATXN3):​c.916_917insA​(p.Gly306GlufsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000302 in 66,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000030 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0000064 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 frameshift
• 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	NM_004993.6	MANE Select	c.916_917insA	p.Gly306GlufsTer12	frameshift	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.871_872insA	p.Gly291GlufsTer12	frameshift	Exon 9 of 10	NP_001121168.1	P54252-4
	ATXN3	NM_001127697.3		c.763_764insA	p.Gly255GlufsTer12	frameshift	Exon 8 of 9	NP_001121169.2	A0A0A0MS38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.916_917insA	p.Gly306GlufsTer12	frameshift	Exon 10 of 11	ENSP00000496695.1	P54252-2
	ATXN3	ENST00000532032.5	TSL:1	c.916_917insA	p.Gly306GlufsTer12	frameshift	Exon 10 of 10	ENSP00000437157.1	P54252-1
	ATXN3	ENST00000503767.5	TSL:1	c.871_872insA	p.Gly291GlufsTer12	frameshift	Exon 9 of 10	ENSP00000426697.1	P54252-4

Frequencies

GnomAD3 genomes AF: 0.0000302 AC: 2 AN: 66138 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000641 AC: 5 AN: 779466 Hom.: 1 Cov.: 50 AF XY: 0.00000254 AC XY: 1 AN XY: 393812

African (AFR) AF: 0.0000828 AC: 1 AN: 12080

American (AMR) AF: 0.00 AC: 0 AN: 19378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15484

East Asian (EAS) AF: 0.00 AC: 0 AN: 34114

South Asian (SAS) AF: 0.00 AC: 0 AN: 50440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2870

European-Non Finnish (NFE) AF: 0.00000689 AC: 4 AN: 580742

Other (OTH) AF: 0.00 AC: 0 AN: 32324

GnomAD4 genome AF: 0.0000302 AC: 2 AN: 66138 Hom.: 0 Cov.: 22 AF XY: 0.0000309 AC XY: 1 AN XY: 32332

African (AFR) AF: 0.000171 AC: 2 AN: 11678

American (AMR) AF: 0.00 AC: 0 AN: 5492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2032

East Asian (EAS) AF: 0.00 AC: 0 AN: 4394

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 168

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 33000

Other (OTH) AF: 0.00 AC: 0 AN: 916

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.80
Mutation Taster		=115/85	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs763461489; hg19: chr14-92537353;