14-92064169-C-T

Variant names:

• chr14-92064169-C-T
• rs709930
• NM_004993.6:c.*151G>A

Variant summary

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

The NM_004993.6(ATXN3):​c.*151G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 525,556 control chromosomes in the GnomAD database, including 18,866 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 0.26 (5377 hom., cov: 33)
  • Exomes 𝑓: 0.26 (13489 hom.)
• Consequence: ATXN3 NM_004993.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 17 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 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.*151G>A		3_prime_UTR	Exon 11 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.*151G>A		3_prime_UTR	Exon 10 of 10	NP_001121168.1	P54252-4
	ATXN3	NM_001127697.3		c.*151G>A		3_prime_UTR	Exon 9 of 9	NP_001121169.2	A0A0A0MS38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.*151G>A		3_prime_UTR	Exon 11 of 11	ENSP00000496695.1	P54252-2
	ATXN3	ENST00000503767.5	TSL:1	c.*151G>A		3_prime_UTR	Exon 10 of 10	ENSP00000426697.1	P54252-4
	ATXN3	ENST00000393287.9	TSL:1	c.*151G>A		3_prime_UTR	Exon 9 of 9	ENSP00000376965.6	A0A0A0MS38

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39784 AN: 151924 Hom.: 5361 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.260 AC: 97157 AN: 373514 Hom.: 13489 Cov.: 5 AF XY: 0.264 AC XY: 51596 AN XY: 195626

African (AFR) AF: 0.319 AC: 3166 AN: 9934

American (AMR) AF: 0.172 AC: 2246 AN: 13082

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 3742 AN: 11594

East Asian (EAS) AF: 0.402 AC: 10688 AN: 26574

South Asian (SAS) AF: 0.354 AC: 9325 AN: 26318

European-Finnish (FIN) AF: 0.220 AC: 8307 AN: 37690

Middle Eastern (MID) AF: 0.282 AC: 464 AN: 1646

European-Non Finnish (NFE) AF: 0.239 AC: 53794 AN: 225320

Other (OTH) AF: 0.254 AC: 5425 AN: 21356

GnomAD4 genome AF: 0.262 AC: 39836 AN: 152042 Hom.: 5377 Cov.: 33 AF XY: 0.262 AC XY: 19489 AN XY: 74322

African (AFR) AF: 0.310 AC: 12842 AN: 41470

American (AMR) AF: 0.186 AC: 2834 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1084 AN: 3470

East Asian (EAS) AF: 0.357 AC: 1846 AN: 5174

South Asian (SAS) AF: 0.350 AC: 1686 AN: 4822

European-Finnish (FIN) AF: 0.233 AC: 2461 AN: 10570

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16239 AN: 67966

Other (OTH) AF: 0.253 AC: 534 AN: 2114

Alfa AF: 0.213 Hom.: 1652

Bravo AF: 0.259

Asia WGS AF: 0.359 AC: 1248 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.83
DANN	Benign	0.73
PhyloP100		-1.1
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: rs709930; hg19: chr14-92530513; COSMIC: COSV61495336;