rs3814834

Positions:

• chr14-92106583-G-A
• chr14-92106583-G-C

Variant summary

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

The ENST00000503767.5(ATXN3):​c.-31C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,607,266 control chromosomes in the GnomAD database, including 12,782 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 0.17 (3181 hom., cov: 30)
  • Exomes 𝑓: 0.11 (9601 hom.)
• Consequence: ATXN3 ENST00000503767.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.180

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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6			upstream_gene_variant		ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2			upstream_gene_variant			NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25349 AN: 150408 Hom.: 3171 Cov.: 30

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.0934

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0744

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0926

Gnomad MID AF: 0.0903

Gnomad NFE AF: 0.0984

Gnomad OTH AF: 0.144

GnomAD3 exomes AF: 0.111 AC: 26567 AN: 239344 Hom.: 2165 AF XY: 0.109 AC XY: 14194 AN XY: 130804

Gnomad AFR exome AF: 0.366

Gnomad AMR exome AF: 0.0538

Gnomad ASJ exome AF: 0.0970

Gnomad EAS exome AF: 0.0735

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0962

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.105 AC: 153076 AN: 1456756 Hom.: 9601 Cov.: 32 AF XY: 0.105 AC XY: 76029 AN XY: 724690

Gnomad4 AFR exome AF: 0.373

Gnomad4 AMR exome AF: 0.0582

Gnomad4 ASJ exome AF: 0.0973

Gnomad4 EAS exome AF: 0.0857

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.0934

Gnomad4 NFE exome AF: 0.0987

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.169 AC: 25385 AN: 150510 Hom.: 3181 Cov.: 30 AF XY: 0.166 AC XY: 12214 AN XY: 73580

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.0930

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.0738

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.0926

Gnomad4 NFE AF: 0.0984

Gnomad4 OTH AF: 0.143

Alfa AF: 0.136 Hom.: 551

Bravo AF: 0.179

Asia WGS AF: 0.138 AC: 478 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3814834; hg19: chr14-92572927; COSMIC: COSV61498058; COSMIC: COSV61498058;