14-92071010-CCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG
• rs193922928
• NM_004993.6:c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_004993.6(ATXN3):​c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG​(p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. 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.

• Frequency:
  • Genomes: 𝑓 0.012 (95 hom., cov: 20)
  • Exomes 𝑓: 0.0014 (15 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004993.6
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1781/142492) while in subpopulation AFR AF = 0.0413 (1501/36302). AF 95% confidence interval is 0.0396. There are 95 homozygotes in GnomAd4. There are 819 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1781 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 10 of 11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1772 AN: 142382 Hom.: 93 Cov.: 20

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.000646

Gnomad SAS AF: 0.00301

Gnomad FIN AF: 0.000506

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.0129

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00140 AC: 1835 AN: 1314392 Hom.: 15 Cov.: 92 AF XY: 0.00149 AC XY: 976 AN XY: 657198

African (AFR) AF: 0.0176 AC: 484 AN: 27558

American (AMR) AF: 0.00247 AC: 100 AN: 40502

Ashkenazi Jewish (ASJ) AF: 0.000492 AC: 12 AN: 24396

East Asian (EAS) AF: 0.000427 AC: 16 AN: 37452

South Asian (SAS) AF: 0.00199 AC: 158 AN: 79484

European-Finnish (FIN) AF: 0.00176 AC: 86 AN: 48882

Middle Eastern (MID) AF: 0.00233 AC: 12 AN: 5148

European-Non Finnish (NFE) AF: 0.000809 AC: 806 AN: 995866

Other (OTH) AF: 0.00292 AC: 161 AN: 55104

GnomAD4 genome AF: 0.0125 AC: 1781 AN: 142492 Hom.: 95 Cov.: 20 AF XY: 0.0118 AC XY: 819 AN XY: 69220

African (AFR) AF: 0.0413 AC: 1501 AN: 36302

American (AMR) AF: 0.00465 AC: 67 AN: 14412

Ashkenazi Jewish (ASJ) AF: 0.000293 AC: 1 AN: 3412

East Asian (EAS) AF: 0.000647 AC: 3 AN: 4634

South Asian (SAS) AF: 0.00302 AC: 13 AN: 4310

European-Finnish (FIN) AF: 0.000506 AC: 5 AN: 9884

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.00247 AC: 164 AN: 66414

Other (OTH) AF: 0.0127 AC: 25 AN: 1962

Alfa AF: 0.00 Hom.: 345

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=80/20	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;