14-92071010-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000644486.2(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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/20 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. G306delinsQQQQQQR) 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 ENST00000644486.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:3 O:1
• 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: Likely_benign. The variant received -6 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 VariationId is 128515.Status of the report is criteria_provided_single_submitter, 1 stars.

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>C	p.Gly306Arg	missense	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.871G>C	p.Gly291Arg	missense	Exon 9 of 10	NP_001121168.1
	ATXN3	NM_001127697.3		c.763G>C	p.Gly255Arg	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>C	p.Gly306Arg	missense	Exon 10 of 11	ENSP00000496695.1
	ATXN3	ENST00000532032.5	TSL:1	c.916G>C	p.Gly306Arg	missense	Exon 10 of 10	ENSP00000437157.1
	ATXN3	ENST00000503767.5	TSL:1	c.871G>C	p.Gly291Arg	missense	Exon 9 of 10	ENSP00000426697.1

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

African (AFR) AF: 0.0524 AC: 1445 AN: 27562

American (AMR) AF: 0.0305 AC: 1235 AN: 40506

Ashkenazi Jewish (ASJ) AF: 0.0454 AC: 1108 AN: 24392

East Asian (EAS) AF: 0.0541 AC: 2024 AN: 37418

South Asian (SAS) AF: 0.0592 AC: 4699 AN: 79438

European-Finnish (FIN) AF: 0.0201 AC: 981 AN: 48882

Middle Eastern (MID) AF: 0.0393 AC: 202 AN: 5142

European-Non Finnish (NFE) AF: 0.0382 AC: 38034 AN: 995550

Other (OTH) AF: 0.0414 AC: 2282 AN: 55076

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

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

African (AFR) AF: 0.0132 AC: 480 AN: 36240

American (AMR) AF: 0.00312 AC: 45 AN: 14408

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 8 AN: 3412

East Asian (EAS) AF: 0.0152 AC: 70 AN: 4610

South Asian (SAS) AF: 0.00395 AC: 17 AN: 4308

European-Finnish (FIN) AF: 0.00121 AC: 12 AN: 9878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00245 AC: 163 AN: 66396

Other (OTH) AF: 0.00715 AC: 14 AN: 1958

⚠️ 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: 0.106 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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ATXN3-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	-	Azorean disease (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.080	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.80
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.048
Sift	Benign	0.15	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.20		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
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

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