14-92071010-C-CCTG

Variant names:

• chr14-92071010-C-CCTG
• rs193922928
• NM_004993.6:c.913_915dupCAG

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_004993.6(ATXN3):​c.913_915dupCAG​(p.Gln305dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,456,684 control chromosomes in the GnomAD database, including 54 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0018 (54 hom.)
• Consequence: ATXN3 NM_004993.6 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004993.6
• BP6: Variant 14-92071010-C-CCTG is Benign according to our data. Variant chr14-92071010-C-CCTG is described in ClinVar as Likely_benign. ClinVar VariationId is 2644468.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 176 AD gene.

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.913_915dupCAG	p.Gln305dup	conservative_inframe_insertion	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.868_870dupCAG	p.Gln290dup	conservative_inframe_insertion	Exon 9 of 10	NP_001121168.1
	ATXN3	NM_001127697.3		c.760_762dupCAG	p.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.913_915dupCAG	p.Gln305dup	conservative_inframe_insertion	Exon 10 of 11	ENSP00000496695.1
	ATXN3	ENST00000532032.5	TSL:1	c.913_915dupCAG	p.Gln305dup	conservative_inframe_insertion	Exon 10 of 10	ENSP00000437157.1
	ATXN3	ENST00000503767.5	TSL:1	c.868_870dupCAG	p.Gln290dup	conservative_inframe_insertion	Exon 9 of 10	ENSP00000426697.1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 175 AN: 142392 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000939

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000695

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000431

Gnomad SAS AF: 0.000464

Gnomad FIN AF: 0.000405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00206

GnomAD4 exome AF: 0.00175 AC: 2301 AN: 1314182 Hom.: 54 Cov.: 92 AF XY: 0.00166 AC XY: 1092 AN XY: 657120

African (AFR) AF: 0.000508 AC: 14 AN: 27554

American (AMR) AF: 0.000815 AC: 33 AN: 40494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24394

East Asian (EAS) AF: 0.000240 AC: 9 AN: 37442

South Asian (SAS) AF: 0.000176 AC: 14 AN: 79472

European-Finnish (FIN) AF: 0.000164 AC: 8 AN: 48892

Middle Eastern (MID) AF: 0.000777 AC: 4 AN: 5148

European-Non Finnish (NFE) AF: 0.00215 AC: 2137 AN: 995696

Other (OTH) AF: 0.00149 AC: 82 AN: 55090

GnomAD4 genome AF: 0.00124 AC: 176 AN: 142502 Hom.: 0 Cov.: 20 AF XY: 0.000910 AC XY: 63 AN XY: 69228

African (AFR) AF: 0.000936 AC: 34 AN: 36310

American (AMR) AF: 0.000694 AC: 10 AN: 14414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.000432 AC: 2 AN: 4634

South Asian (SAS) AF: 0.000464 AC: 2 AN: 4310

European-Finnish (FIN) AF: 0.000405 AC: 4 AN: 9884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00181 AC: 120 AN: 66414

Other (OTH) AF: 0.00204 AC: 4 AN: 1962

Alfa AF: 0.00 Hom.: 345

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATXN3: BS1

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=78/22	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;