rs10873415

Variant names:

• chr14-92091827-G-A
• rs10873415
• NM_004993.6:c.387+1425C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Machado-Joseph disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Machado-Joseph disease type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000303901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004993.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	NM_004993.6	MANE Select	c.387+1425C>T		intron	N/A	NP_004984.2
	ATXN3	NM_001127696.2		c.342+1425C>T		intron	N/A	NP_001121168.1	P54252-4
	ATXN3	NM_001127697.3		c.235-3010C>T		intron	N/A	NP_001121169.2	A0A0A0MS38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.387+1425C>T		intron	N/A	ENSP00000496695.1	P54252-2
	ATXN3	ENST00000532032.5	TSL:1	c.387+1425C>T		intron	N/A	ENSP00000437157.1	P54252-1
	ATXN3	ENST00000503767.5	TSL:1	c.342+1425C>T		intron	N/A	ENSP00000426697.1	P54252-4

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

African (AFR) AF: 0.873 AC: 36084 AN: 41322

American (AMR) AF: 0.802 AC: 12215 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 2734 AN: 3472

East Asian (EAS) AF: 0.554 AC: 2849 AN: 5138

South Asian (SAS) AF: 0.826 AC: 3961 AN: 4796

European-Finnish (FIN) AF: 0.740 AC: 7726 AN: 10446

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.774 AC: 52530 AN: 67908

Other (OTH) AF: 0.802 AC: 1689 AN: 2106

Alfa AF: 0.779 Hom.: 126954

Bravo AF: 0.799

Asia WGS AF: 0.744 AC: 2585 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.34
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10873415; hg19: chr14-92558171;