rs10873415

Positions:

• chr14-92091827-G-A
• chr14-92091827-G-C

Variant summary

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

The NM_004993.6(ATXN3):​c.387+1425C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 151,630 control chromosomes in the GnomAD database, including 48,353 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 0.80 (48353 hom., cov: 28)
• Consequence: ATXN3 NM_004993.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.301

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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.387+1425C>T		intron_variant		ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.387+1425C>T		intron_variant			NM_004993.6	ENSP00000496695	P1

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120633 AN: 151512 Hom.: 48293 Cov.: 28

Gnomad AFR AF: 0.873

Gnomad AMI AF: 0.811

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.825

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.774

Gnomad OTH AF: 0.799

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.796 AC: 120753 AN: 151630 Hom.: 48353 Cov.: 28 AF XY: 0.794 AC XY: 58783 AN XY: 74064

Gnomad4 AFR AF: 0.873

Gnomad4 AMR AF: 0.802

Gnomad4 ASJ AF: 0.787

Gnomad4 EAS AF: 0.554

Gnomad4 SAS AF: 0.826

Gnomad4 FIN AF: 0.740

Gnomad4 NFE AF: 0.774

Gnomad4 OTH AF: 0.802

Alfa AF: 0.779 Hom.: 47905

Bravo AF: 0.799

Asia WGS AF: 0.744 AC: 2585 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.34

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: rs10873415; hg19: chr14-92558171;