NM_004993.6:c.891A>C

Variant names:

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

Variant summary

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

The NM_004993.6(ATXN3):​c.891A>C​(p.Gln297His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 537,314 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Synonymous variant affecting the same amino acid position (i.e. Q297Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: ATXN3 NM_004993.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.273
• Publications: 0 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=0.08118275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.891A>C	p.Gln297His	missense_variant	Exon 10 of 11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.891A>C	p.Gln297His	missense_variant	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000186 AC: 1 AN: 537314 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 270022

African (AFR) AF: 0.00 AC: 0 AN: 15048

American (AMR) AF: 0.00 AC: 0 AN: 16450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9786

East Asian (EAS) AF: 0.00 AC: 0 AN: 22186

South Asian (SAS) AF: 0.00 AC: 0 AN: 45748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1880

European-Non Finnish (NFE) AF: 0.00000260 AC: 1 AN: 385288

Other (OTH) AF: 0.00 AC: 0 AN: 22726

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T;T;.;.;T;.;.;.;.;.;T;T;T;T;T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.82	.;T;D;T;T;T;T;T;T;D;T;T;T;T;D;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.27
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	.;.;N;.;.;N;N;N;N;N;N;N;N;N;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0020	.;.;D;.;.;D;D;D;D;D;D;D;D;D;.;.
Sift4G	Uncertain	0.011	.;D;T;D;D;D;D;D;D;.;.;.;.;.;D;.
Polyphen		0.71	P;.;.;.;P;.;.;B;.;.;.;.;.;.;.;.
Vest4		0.49, 0.49, 0.51, 0.49, 0.47, 0.49, 0.50, 0.42, 0.49
MutPred		0.16		Loss of MoRF binding (P = 0.1302);.;.;.;Loss of MoRF binding (P = 0.1302);.;.;.;Loss of MoRF binding (P = 0.1302);.;.;.;.;.;.;.;
MVP		0.59
MPC		0.21
ClinPred		0.12	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.099
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;