14-92071010-C-T

Variant names:

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

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.916G>A​(p.Gly306Arg) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in 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: 0.0000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 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=0.10950148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.916G>A	p.Gly306Arg	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.916G>A	p.Gly306Arg	missense_variant	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000228 AC: 3 AN: 1314556 Hom.: 0 Cov.: 50 AF XY: 0.00000304 AC XY: 2 AN XY: 657300

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: 0.00000301 AC: 3 AN: 995974

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.3
DANN	Benign	0.51
DEOGEN2	Benign	0.038	T;T;.;.;T;.;.;.;.;.;T;T;T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.080	.;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.80
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.28	.;.;N;.;.;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.048
Sift	Benign	0.15	.;.;T;.;.;T;T;T;D;T;T;T;T;T;.
Sift4G	Benign	0.66	.;T;T;T;T;T;T;T;T;.;.;.;.;.;T
Polyphen		0.0	B;.;.;.;B;.;.;B;.;.;.;.;.;.;.
Vest4		0.23, 0.23, 0.24, 0.23, 0.21, 0.25, 0.20, 0.27
MutPred		0.20		Gain of catalytic residue at L308 (P = 0.0509);.;.;.;Gain of catalytic residue at L308 (P = 0.0509);.;.;.;Gain of catalytic residue at L308 (P = 0.0509);.;.;.;.;.;.;
MVP		0.54
MPC		0.26
ClinPred		0.54	D
GERP RS		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.11
Mutation Taster		=89/11	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;