rs3814834

Variant names:

• chr14-92106583-G-A
• rs3814834
• ENST00000503767.5:c.-31C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-92106583-G-A
• chr14-92106583-G-C

Variant summary

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

The ENST00000503767.5(ATXN3):​c.-31C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,607,266 control chromosomes in the GnomAD database, including 12,782 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 0.17 (3181 hom., cov: 30)
  • Exomes 𝑓: 0.11 (9601 hom.)
• Consequence: ATXN3 ENST00000503767.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.180
• Publications: 12 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000503767.5. 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.-31C>T		upstream_gene	N/A	NP_004984.2
	ATXN3	NM_001127696.2		c.-31C>T		upstream_gene	N/A	NP_001121168.1	P54252-4
	ATXN3	NM_001127697.3		c.-31C>T		upstream_gene	N/A	NP_001121169.2	A0A0A0MS38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000503767.5	TSL:1	c.-31C>T		5_prime_UTR	Exon 1 of 10	ENSP00000426697.1	P54252-4
	ATXN3	ENST00000393287.9	TSL:1	c.-31C>T		5_prime_UTR	Exon 1 of 9	ENSP00000376965.6	A0A0A0MS38
	ATXN3	ENST00000340660.10	TSL:1	c.-31C>T		5_prime_UTR	Exon 1 of 10	ENSP00000339110.6	P54252-3

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25349 AN: 150408 Hom.: 3171 Cov.: 30

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.0934

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0744

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0926

Gnomad MID AF: 0.0903

Gnomad NFE AF: 0.0984

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.111 AC: 26567 AN: 239344 AF XY: 0.109

Gnomad AFR exome AF: 0.366

Gnomad AMR exome AF: 0.0538

Gnomad ASJ exome AF: 0.0970

Gnomad EAS exome AF: 0.0735

Gnomad FIN exome AF: 0.0962

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.105 AC: 153076 AN: 1456756 Hom.: 9601 Cov.: 32 AF XY: 0.105 AC XY: 76029 AN XY: 724690

African (AFR) AF: 0.373 AC: 12378 AN: 33184

American (AMR) AF: 0.0582 AC: 2587 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.0973 AC: 2530 AN: 25996

East Asian (EAS) AF: 0.0857 AC: 3379 AN: 39420

South Asian (SAS) AF: 0.118 AC: 10108 AN: 85896

European-Finnish (FIN) AF: 0.0934 AC: 4950 AN: 52976

Middle Eastern (MID) AF: 0.129 AC: 740 AN: 5746

European-Non Finnish (NFE) AF: 0.0987 AC: 109461 AN: 1109002

Other (OTH) AF: 0.116 AC: 6943 AN: 60100

GnomAD4 genome AF: 0.169 AC: 25385 AN: 150510 Hom.: 3181 Cov.: 30 AF XY: 0.166 AC XY: 12214 AN XY: 73580

African (AFR) AF: 0.357 AC: 14532 AN: 40650

American (AMR) AF: 0.0930 AC: 1413 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3460

East Asian (EAS) AF: 0.0738 AC: 376 AN: 5094

South Asian (SAS) AF: 0.123 AC: 584 AN: 4762

European-Finnish (FIN) AF: 0.0926 AC: 967 AN: 10440

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.0984 AC: 6653 AN: 67630

Other (OTH) AF: 0.143 AC: 300 AN: 2096

Alfa AF: 0.136 Hom.: 551

Bravo AF: 0.179

Asia WGS AF: 0.138 AC: 478 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.83
PhyloP100		0.18
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3814834;

hg19: chr14-92572927;

COSMIC: COSV61498058;

COSMIC: COSV61498058;