NM_004993.6:c.388-894A>G

Variant names:

• chr14-92089711-T-C
• rs17807815
• NM_004993.6:c.388-894A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004993.6(ATXN3):​c.388-894A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0767 in 152,258 control chromosomes in the GnomAD database, including 588 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 0.077 (588 hom., cov: 32)
• Consequence: ATXN3 NM_004993.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 9 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.138 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	NM_004993.6	MANE Select	c.388-894A>G		intron	N/A	NP_004984.2
	ATXN3	NM_001127696.2		c.343-894A>G		intron	N/A	NP_001121168.1
	ATXN3	NM_001127697.3		c.235-894A>G		intron	N/A	NP_001121169.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.388-894A>G		intron	N/A	ENSP00000496695.1
	ATXN3	ENST00000532032.5	TSL:1	c.388-894A>G		intron	N/A	ENSP00000437157.1
	ATXN3	ENST00000503767.5	TSL:1	c.343-894A>G		intron	N/A	ENSP00000426697.1

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 11663 AN: 152140 Hom.: 583 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0831

Gnomad FIN AF: 0.0619

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.101

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

GnomAD4 genome AF: 0.0767 AC: 11685 AN: 152258 Hom.: 588 Cov.: 32 AF XY: 0.0766 AC XY: 5705 AN XY: 74450

African (AFR) AF: 0.0211 AC: 876 AN: 41554

American (AMR) AF: 0.143 AC: 2185 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 362 AN: 3470

East Asian (EAS) AF: 0.0261 AC: 135 AN: 5182

South Asian (SAS) AF: 0.0844 AC: 407 AN: 4824

European-Finnish (FIN) AF: 0.0619 AC: 657 AN: 10612

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0991 AC: 6739 AN: 68016

Other (OTH) AF: 0.105 AC: 222 AN: 2116

Alfa AF: 0.0934 Hom.: 1698

Bravo AF: 0.0782

Asia WGS AF: 0.0620 AC: 217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.0
DANN	Benign	0.74
PhyloP100		-1.5
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: rs17807815; hg19: chr14-92556055;