rs12588287

Variant names:

• chr14-92070615-T-A
• rs12588287
• NM_004993.6:c.991+320A>T

Your query was ambiguous. Multiple possible variants found:

• chr14-92070615-T-A
• chr14-92070615-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004993.6(ATXN3):​c.991+320A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000201 in 497,432 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: ATXN3 NM_004993.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.134
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.991+320A>T		intron_variant	Intron 10 of 10	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.991+320A>T		intron_variant	Intron 10 of 10		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000201 AC: 1 AN: 497432 Hom.: 0 AF XY: 0.00000391 AC XY: 1 AN XY: 256048

African (AFR) AF: 0.00 AC: 0 AN: 12204

American (AMR) AF: 0.00 AC: 0 AN: 13490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12864

East Asian (EAS) AF: 0.0000385 AC: 1 AN: 25944

South Asian (SAS) AF: 0.00 AC: 0 AN: 37716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1990

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 343708

Other (OTH) AF: 0.00 AC: 0 AN: 26164

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.97
DANN	Benign	0.80
PhyloP100		-0.13

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: rs12588287; hg19: chr14-92536959;