14-92071010-CCTGCTG-CCTGCTGCTG

Position:

• chr14-92071010-CCTGCTG-CCTGCTGCTG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004993.6(ATXN3):​c.915_916insCAG​(p.Gln305dup) variant causes a 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 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 Likely_benign. Variant got -6 ACMG points.

• 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 id is 2644468.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 176 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.915_916insCAG	p.Gln305dup	inframe_insertion	10/11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAG	p.Gln305dup	inframe_insertion	10/11		NM_004993.6	ENSP00000496695	P1

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

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000815

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000240

Gnomad4 SAS exome AF: 0.000176

Gnomad4 FIN exome AF: 0.000164

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00149

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

Gnomad4 AFR AF: 0.000936

Gnomad4 AMR AF: 0.000694

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000432

Gnomad4 SAS AF: 0.000464

Gnomad4 FIN AF: 0.000405

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00204

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

ATXN3: BS1 -

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;