14-92070615-T-C

Variant names:

• chr14-92070615-T-C
• rs12588287
• NM_004993.6:c.991+320A>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.991+320A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 647,474 control chromosomes in the GnomAD database, including 18,780 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 0.22 (3944 hom., cov: 32)
  • Exomes 𝑓: 0.23 (14836 hom.)
• Consequence: ATXN3 NM_004993.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.134
• Publications: 18 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 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.991+320A>G		intron	N/A	NP_004984.2
	ATXN3	NM_001127696.2		c.946+320A>G		intron	N/A	NP_001121168.1	P54252-4
	ATXN3	NM_001127697.3		c.838+320A>G		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.991+320A>G		intron	N/A	ENSP00000496695.1	P54252-2
	ATXN3	ENST00000503767.5	TSL:1	c.946+320A>G		intron	N/A	ENSP00000426697.1	P54252-4
	ATXN3	ENST00000393287.9	TSL:1	c.838+320A>G		intron	N/A	ENSP00000376965.6	A0A0A0MS38

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33508 AN: 151946 Hom.: 3946 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.230 AC: 114157 AN: 495410 Hom.: 14836 AF XY: 0.235 AC XY: 59891 AN XY: 255056

African (AFR) AF: 0.150 AC: 1825 AN: 12180

American (AMR) AF: 0.156 AC: 2105 AN: 13472

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 4057 AN: 12838

East Asian (EAS) AF: 0.454 AC: 11749 AN: 25860

South Asian (SAS) AF: 0.307 AC: 11562 AN: 37612

European-Finnish (FIN) AF: 0.213 AC: 4960 AN: 23274

Middle Eastern (MID) AF: 0.249 AC: 492 AN: 1974

European-Non Finnish (NFE) AF: 0.209 AC: 71474 AN: 342140

Other (OTH) AF: 0.228 AC: 5933 AN: 26060

GnomAD4 genome AF: 0.220 AC: 33505 AN: 152064 Hom.: 3944 Cov.: 32 AF XY: 0.221 AC XY: 16393 AN XY: 74338

African (AFR) AF: 0.160 AC: 6641 AN: 41500

American (AMR) AF: 0.166 AC: 2528 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1093 AN: 3466

East Asian (EAS) AF: 0.424 AC: 2185 AN: 5154

South Asian (SAS) AF: 0.317 AC: 1526 AN: 4818

European-Finnish (FIN) AF: 0.233 AC: 2461 AN: 10582

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16302 AN: 67962

Other (OTH) AF: 0.220 AC: 464 AN: 2110

Alfa AF: 0.238 Hom.: 6921

Bravo AF: 0.212

Asia WGS AF: 0.330 AC: 1146 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	1.2
DANN	Benign	0.79
PhyloP100		-0.13
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: rs12588287; hg19: chr14-92536959;