14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004993.6(ATXN3):c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG(p.Gln296_Gln305dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (202 hom., cov: 20)
  • Exomes 𝑓: 0.034 (4293 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.168

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is described in ClinVar as [Benign]. Clinvar id is 218660.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0391 (5565/142438) while in subpopulation NFE AF= 0.0474 (3144/66386). AF 95% confidence interval is 0.046. There are 202 homozygotes in gnomad4. There are 2539 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd at 5555 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln296_Gln305dup	inframe_insertion	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln296_Gln305dup	inframe_insertion	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5555 AN: 142328 Hom.: 200 Cov.: 20

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.0193

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.0223

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.0229

Gnomad MID AF: 0.0296

Gnomad NFE AF: 0.0474

Gnomad OTH AF: 0.0346

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0336 AC: 44006 AN: 1309066 Hom.: 4293 Cov.: 92 AF XY: 0.0340 AC XY: 22226 AN XY: 654526

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.0208

Gnomad4 ASJ exome AF: 0.0221

Gnomad4 EAS exome AF: 0.0308

Gnomad4 SAS exome AF: 0.0283

Gnomad4 FIN exome AF: 0.0250

Gnomad4 NFE exome AF: 0.0355

Gnomad4 OTH exome AF: 0.0325

GnomAD4 genome AF: 0.0391 AC: 5565 AN: 142438 Hom.: 202 Cov.: 20 AF XY: 0.0367 AC XY: 2539 AN XY: 69194

Gnomad4 AFR AF: 0.0381

Gnomad4 AMR AF: 0.0273

Gnomad4 ASJ AF: 0.0223

Gnomad4 EAS AF: 0.0248

Gnomad4 SAS AF: 0.0316

Gnomad4 FIN AF: 0.0229

Gnomad4 NFE AF: 0.0474

Gnomad4 OTH AF: 0.0342

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

May 05, 2015

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922928; hg19: chr14-92537354;