rs12895357

Variant names:

• chr14-92071010-C-A
• rs12895357
• NM_004993.6:c.916G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-92071010-C-A
• chr14-92071010-C-G
• chr14-92071010-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000644486.2(ATXN3):​c.916G>T​(p.Gly306Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G306delinsQQQQQQR) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 ENST00000644486.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.802
• Publications: 39 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1315445).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000644486.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	NM_004993.6	MANE Select	c.916G>T	p.Gly306Trp	missense	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.871G>T	p.Gly291Trp	missense	Exon 9 of 10	NP_001121168.1
	ATXN3	NM_001127697.3		c.763G>T	p.Gly255Trp	missense	Exon 8 of 9	NP_001121169.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.916G>T	p.Gly306Trp	missense	Exon 10 of 11	ENSP00000496695.1
	ATXN3	ENST00000532032.5	TSL:1	c.916G>T	p.Gly306Trp	missense	Exon 10 of 10	ENSP00000437157.1
	ATXN3	ENST00000503767.5	TSL:1	c.871G>T	p.Gly291Trp	missense	Exon 9 of 10	ENSP00000426697.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.61e-7 AC: 1 AN: 1314554 Hom.: 0 Cov.: 50 AF XY: 0.00000152 AC XY: 1 AN XY: 657298

African (AFR) AF: 0.00 AC: 0 AN: 27564

American (AMR) AF: 0.00 AC: 0 AN: 40510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24398

East Asian (EAS) AF: 0.00 AC: 0 AN: 37450

South Asian (SAS) AF: 0.00 AC: 0 AN: 79492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5148

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 995972

Other (OTH) AF: 0.00 AC: 0 AN: 55108

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 161

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.46
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.80
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.054
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.21		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.55
MPC		0.26
ClinPred		0.73	D
GERP RS		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.13
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12895357; hg19: chr14-92537354;