14-92071010-CCTGCTGCTGCTG-CCTGCTGCTG

Variant names:

• chr14-92071010-CCTG-C
• rs193922928
• NM_004993.6:c.913_915delCAG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_004993.6(ATXN3):​c.913_915delCAG​(p.Gln305del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000635 in 1,448,172 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: ATXN3 NM_004993.6 conservative_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.902
• 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, 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 -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004993.6
• BS2: High AC in GnomAd4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	NM_004993.6	MANE Select	c.913_915delCAG	p.Gln305del	conservative_inframe_deletion	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.868_870delCAG	p.Gln290del	conservative_inframe_deletion	Exon 9 of 10	NP_001121168.1	P54252-4
	ATXN3	NM_001127697.3		c.760_762delCAG	p.Gln254del	conservative_inframe_deletion	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.913_915delCAG	p.Gln305del	conservative_inframe_deletion	Exon 10 of 11	ENSP00000496695.1	P54252-2
	ATXN3	ENST00000532032.5	TSL:1	c.913_915delCAG	p.Gln305del	conservative_inframe_deletion	Exon 10 of 10	ENSP00000437157.1	P54252-1
	ATXN3	ENST00000503767.5	TSL:1	c.868_870delCAG	p.Gln290del	conservative_inframe_deletion	Exon 9 of 10	ENSP00000426697.1	P54252-4

Frequencies

GnomAD3 genomes AF: 0.0000351 AC: 5 AN: 142386 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000829

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: 0.0000301

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000666 AC: 87 AN: 1305786 Hom.: 0 AF XY: 0.0000674 AC XY: 44 AN XY: 652944

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000146 AC: 4 AN: 27374

American (AMR) AF: 0.000125 AC: 5 AN: 40140

Ashkenazi Jewish (ASJ) AF: 0.0000412 AC: 1 AN: 24270

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36966

South Asian (SAS) AF: 0.000101 AC: 8 AN: 78980

European-Finnish (FIN) AF: 0.000391 AC: 19 AN: 48598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5120

European-Non Finnish (NFE) AF: 0.0000465 AC: 46 AN: 989578

Other (OTH) AF: 0.0000548 AC: 3 AN: 54760

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000351 AC: 5 AN: 142386 Hom.: 0 Cov.: 20 AF XY: 0.0000289 AC XY: 2 AN XY: 69096

African (AFR) AF: 0.0000829 AC: 3 AN: 36198

American (AMR) AF: 0.00 AC: 0 AN: 14398

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4640

South Asian (SAS) AF: 0.00 AC: 0 AN: 4314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66418

Other (OTH) AF: 0.00 AC: 0 AN: 1940

Alfa AF: 0.00 Hom.: 345

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs193922928; hg19: chr14-92537354; COSMIC: COSV61494854;