chr14-92063938-C-A

Position:

• chr14-92063938-C-A

Variant summary

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

The NM_004993.6(ATXN3):​c.*382G>T 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 158,982 control chromosomes in the GnomAD database, including 5,581 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 (5390 hom., cov: 32)
  • Exomes 𝑓: 0.22 (191 hom.)
• Consequence: ATXN3 NM_004993.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.404

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.*382G>T		3_prime_UTR_variant	11/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.*382G>T		3_prime_UTR_variant	11/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39826 AN: 151826 Hom.: 5374 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.219 AC: 1542 AN: 7038 Hom.: 191 Cov.: 0 AF XY: 0.228 AC XY: 832 AN XY: 3656

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.346

Gnomad4 EAS exome AF: 0.351

Gnomad4 SAS exome AF: 0.287

Gnomad4 FIN exome AF: 0.226

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.262 AC: 39878 AN: 151944 Hom.: 5390 Cov.: 32 AF XY: 0.263 AC XY: 19512 AN XY: 74290

Gnomad4 AFR AF: 0.311

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.356

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.253

Alfa AF: 0.228 Hom.: 4195

Bravo AF: 0.260

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	-0.92
CADD	Benign	0.40
DANN	Benign	0.35

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: rs910369; hg19: chr14-92530282; COSMIC: COSV105232966; COSMIC: COSV105232966;