14-92071009-C-CG

Variant names:

• chr14-92071009-C-CG
• rs763461489
• NM_004993.6:c.916_917insC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_004993.6(ATXN3):​c.916_917insC​(p.Gly306AlafsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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 0.48 (3821 hom., cov: 22)
  • Exomes 𝑓: 0.36 (39001 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 14-92071009-C-CG is Benign according to our data. Variant chr14-92071009-C-CG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402402.

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_917insC	p.Gly306AlafsTer12	frameshift	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.871_872insC	p.Gly291AlafsTer12	frameshift	Exon 9 of 10	NP_001121168.1	P54252-4
	ATXN3	NM_001127697.3		c.763_764insC	p.Gly255AlafsTer12	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_917insC	p.Gly306AlafsTer12	frameshift	Exon 10 of 11	ENSP00000496695.1	P54252-2
	ATXN3	ENST00000532032.5	TSL:1	c.916_917insC	p.Gly306AlafsTer12	frameshift	Exon 10 of 10	ENSP00000437157.1	P54252-1
	ATXN3	ENST00000503767.5	TSL:1	c.871_872insC	p.Gly291AlafsTer12	frameshift	Exon 9 of 10	ENSP00000426697.1	P54252-4

Frequencies

GnomAD3 genomes AF: 0.479 AC: 31454 AN: 65716 Hom.: 3825 Cov.: 22

Gnomad AFR AF: 0.475

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.479

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.360 AC: 279659 AN: 776368 Hom.: 39001 Cov.: 50 AF XY: 0.361 AC XY: 141447 AN XY: 392262

African (AFR) AF: 0.234 AC: 2777 AN: 11892

American (AMR) AF: 0.236 AC: 4550 AN: 19312

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 6561 AN: 15406

East Asian (EAS) AF: 0.427 AC: 14522 AN: 34014

South Asian (SAS) AF: 0.380 AC: 19068 AN: 50242

European-Finnish (FIN) AF: 0.329 AC: 10508 AN: 31950

Middle Eastern (MID) AF: 0.397 AC: 1134 AN: 2858

European-Non Finnish (NFE) AF: 0.361 AC: 209095 AN: 578514

Other (OTH) AF: 0.356 AC: 11444 AN: 32180

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.479 AC: 31448 AN: 65706 Hom.: 3821 Cov.: 22 AF XY: 0.477 AC XY: 15334 AN XY: 32146

African (AFR) AF: 0.475 AC: 5441 AN: 11444

American (AMR) AF: 0.437 AC: 2390 AN: 5468

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1082 AN: 2026

East Asian (EAS) AF: 0.462 AC: 2020 AN: 4372

South Asian (SAS) AF: 0.540 AC: 1440 AN: 2668

European-Finnish (FIN) AF: 0.453 AC: 2401 AN: 5296

Middle Eastern (MID) AF: 0.494 AC: 77 AN: 156

European-Non Finnish (NFE) AF: 0.484 AC: 15938 AN: 32928

Other (OTH) AF: 0.480 AC: 436 AN: 908

Alfa AF: 0.119 Hom.: 383

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not specified (5)
-	-	1	ATXN3-related disorder (1)
-	1	-	Azorean disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.80
Mutation Taster		=154/46	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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; COSMIC: COSV61497794; COSMIC: COSV61497794;