rs12588287

Positions:

• chr14-92070615-T-C

Variant summary

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

The NM_004993.6(ATXN3):​c.991+320A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 647,474 control chromosomes in the GnomAD database, including 18,780 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 0.22 (3944 hom., cov: 32)
  • Exomes 𝑓: 0.23 (14836 hom.)
• Consequence: ATXN3 NM_004993.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.134

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.991+320A>G		intron_variant		ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.991+320A>G		intron_variant			NM_004993.6	ENSP00000496695	P1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33508 AN: 151946 Hom.: 3946 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.230 AC: 114157 AN: 495410 Hom.: 14836 AF XY: 0.235 AC XY: 59891 AN XY: 255056

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.316

Gnomad4 EAS exome AF: 0.454

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.209

Gnomad4 OTH exome AF: 0.228

GnomAD4 genome AF: 0.220 AC: 33505 AN: 152064 Hom.: 3944 Cov.: 32 AF XY: 0.221 AC XY: 16393 AN XY: 74338

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.315

Gnomad4 EAS AF: 0.424

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.240

Gnomad4 OTH AF: 0.220

Alfa AF: 0.214 Hom.: 774

Bravo AF: 0.212

Asia WGS AF: 0.330 AC: 1146 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.79

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: rs12588287; hg19: chr14-92536959;