14-92071010-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004993.6(ATXN3):c.916G>C(p.Gly306Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 142,372 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G306QQQQQQR) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 22)
  • Exomes 𝑓: 0.040 (2689 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: -0.802

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002918005).
• BP6: Variant 14-92071010-C-G is Benign according to our data. Variant chr14-92071010-C-G is described in ClinVar as [Benign]. Clinvar id is 128515.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-92071010-C-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 809 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.916G>C	p.Gly306Arg	missense_variant	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.916G>C	p.Gly306Arg	missense_variant	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.00569 AC: 809 AN: 142262 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00313

Gnomad ASJ AF: 0.00234

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.00417

Gnomad FIN AF: 0.00121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00671

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0396 AC: 52010 AN: 1313966 Hom.: 2689 Cov.: 50 AF XY: 0.0390 AC XY: 25632 AN XY: 656968

Gnomad4 AFR exome AF: 0.0524

Gnomad4 AMR exome AF: 0.0305

Gnomad4 ASJ exome AF: 0.0454

Gnomad4 EAS exome AF: 0.0541

Gnomad4 SAS exome AF: 0.0592

Gnomad4 FIN exome AF: 0.0201

Gnomad4 NFE exome AF: 0.0382

Gnomad4 OTH exome AF: 0.0414

GnomAD4 genome AF: 0.00568 AC: 809 AN: 142372 Hom.: 4 Cov.: 22 AF XY: 0.00568 AC XY: 393 AN XY: 69160

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.00312

Gnomad4 ASJ AF: 0.00234

Gnomad4 EAS AF: 0.0152

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.00121

Gnomad4 NFE AF: 0.00245

Gnomad4 OTH AF: 0.00715

Alfa AF: 0.106 Hom.: 161

Bravo AF: 0.212

TwinsUK AF: 0.235 AC: 872

ALSPAC AF: 0.239 AC: 922

ESP6500AA AF: 0.113 AC: 496

ESP6500EA AF: 0.188 AC: 1619

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

ATXN3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Azorean disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	7.2
Dann	Benign	0.53
DEOGEN2	Benign	0.038	T;T;.;.;T;.;.;.;.;.;T;T;T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.021	N
MetaRNN	Benign	0.0028	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.27	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		0.61	D
GERP RS		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12895357; hg19: chr14-92537354; COSMIC: COSV61494701; COSMIC: COSV61494701;