14-92064169-C-T

Position:

• chr14-92064169-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004993.6(ATXN3):​c.*151G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 525,556 control chromosomes in the GnomAD database, including 18,866 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (5377 hom., cov: 33)
  • Exomes 𝑓: 0.26 (13489 hom.)
• Consequence: ATXN3 NM_004993.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.*151G>A		3_prime_UTR_variant	11/11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486	c.*151G>A		3_prime_UTR_variant	11/11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39784 AN: 151924 Hom.: 5361 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.260 AC: 97157 AN: 373514 Hom.: 13489 Cov.: 5 AF XY: 0.264 AC XY: 51596 AN XY: 195626

Gnomad4 AFR exome AF: 0.319

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.402

Gnomad4 SAS exome AF: 0.354

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.254

GnomAD4 genome AF: 0.262 AC: 39836 AN: 152042 Hom.: 5377 Cov.: 33 AF XY: 0.262 AC XY: 19489 AN XY: 74322

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.253

Alfa AF: 0.201 Hom.: 1011

Bravo AF: 0.259

Asia WGS AF: 0.359 AC: 1248 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.83
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs709930; hg19: chr14-92530513; COSMIC: COSV61495336;