rs12896583

Variant names:

• chr14-92071035-T-C
• rs12896583
• NM_004993.6:c.891A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-92071035-T-C
• chr14-92071035-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001164778.2(ATXN3):​c.406A>G​(p.Thr136Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (2 hom., cov: 0)
  • Exomes 𝑓: 0.19 (273 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_001164778.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.273
• 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=-0.86).
• BP6: Variant 14-92071035-T-C is Benign according to our data. Variant chr14-92071035-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 128514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164778.2. 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.891A>G	p.Gln297Gln	synonymous	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001164778.2		c.406A>G	p.Thr136Ala	missense	Exon 6 of 7	NP_001158250.1
	ATXN3	NM_001164776.2		c.253A>G	p.Thr85Ala	missense	Exon 4 of 5	NP_001158248.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.891A>G	p.Gln297Gln	synonymous	Exon 10 of 11	ENSP00000496695.1	P54252-2
	ATXN3	ENST00000532032.5	TSL:1	c.891A>G	p.Gln297Gln	synonymous	Exon 10 of 10	ENSP00000437157.1	P54252-1
	ATXN3	ENST00000503767.5	TSL:1	c.846A>G	p.Gln282Gln	synonymous	Exon 9 of 10	ENSP00000426697.1	P54252-4

Frequencies

GnomAD3 genomes AF: 0.0343 AC: 686 AN: 20002 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0128

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.00542

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0504

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.188 AC: 94896 AN: 503886 Hom.: 273 Cov.: 47 AF XY: 0.180 AC XY: 45777 AN XY: 254024

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.239 AC: 3383 AN: 14172

American (AMR) AF: 0.151 AC: 2406 AN: 15940

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 1326 AN: 9274

East Asian (EAS) AF: 0.0741 AC: 1604 AN: 21634

South Asian (SAS) AF: 0.112 AC: 4929 AN: 43986

European-Finnish (FIN) AF: 0.112 AC: 1957 AN: 17492

Middle Eastern (MID) AF: 0.157 AC: 268 AN: 1702

European-Non Finnish (NFE) AF: 0.210 AC: 75381 AN: 358210

Other (OTH) AF: 0.170 AC: 3642 AN: 21476

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0344 AC: 689 AN: 20016 Hom.: 2 Cov.: 0 AF XY: 0.0358 AC XY: 365 AN XY: 10184

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.119 AC: 455 AN: 3838

American (AMR) AF: 0.0220 AC: 35 AN: 1592

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 6 AN: 470

East Asian (EAS) AF: 0.0168 AC: 33 AN: 1968

South Asian (SAS) AF: 0.0146 AC: 16 AN: 1094

European-Finnish (FIN) AF: 0.00542 AC: 10 AN: 1846

Middle Eastern (MID) AF: 0.0278 AC: 1 AN: 36

European-Non Finnish (NFE) AF: 0.0135 AC: 119 AN: 8792

Other (OTH) AF: 0.0543 AC: 14 AN: 258

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0375 Hom.: 77

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ATXN3-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.42
DANN	Benign	0.29
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs12896583; hg19: chr14-92537379; COSMIC: COSV61494112;