NM_004993.6:c.947G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004993.6(ATXN3):c.947G>A(p.Cys316Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000728 in 1,236,132 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C316W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000094 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ATXN3
NM_004993.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.256

Publications

0 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
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

ATXN3 links:

ENSG00000303901 (HGNC:):

ENSG00000303901 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035816103).

BS2

High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004993.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN3	NM_004993.6	MANE Select	c.947G>A	p.Cys316Tyr	missense	Exon 10 of 11	NP_004984.2
ATXN3	NM_001127696.2		c.902G>A	p.Cys301Tyr	missense	Exon 9 of 10	NP_001121168.1	P54252-4
ATXN3	NM_001127697.3		c.794G>A	p.Cys265Tyr	missense	Exon 8 of 9	NP_001121169.2	A0A0A0MS38

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN3	ENST00000644486.2	MANE Select	c.947G>A	p.Cys316Tyr	missense	Exon 10 of 11	ENSP00000496695.1	P54252-2
ATXN3	ENST00000532032.5	TSL:1	c.947G>A	p.Cys316Tyr	missense	Exon 10 of 10	ENSP00000437157.1	P54252-1
ATXN3	ENST00000503767.5	TSL:1	c.902G>A	p.Cys301Tyr	missense	Exon 9 of 10	ENSP00000426697.1	P54252-4

Frequencies

GnomAD3 genomes

AF:

0.0000941

AC:

AN:

53110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00104

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000503

AC:

AN:

198912

AF XY:

0.00000910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.00000338

AC:

AN:

1183022

Hom.:

Cov.:

AF XY:

0.00000345

AC XY:

AN XY:

580468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24806

American (AMR)

AF:

0.0000948

AC:

AN:

31642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17116

East Asian (EAS)

AF:

0.00

AC:

AN:

21350

South Asian (SAS)

AF:

0.00

AC:

AN:

54670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

949566

Other (OTH)

AF:

0.0000227

AC:

AN:

44126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000941

AC:

AN:

53110

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

26014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

10538

American (AMR)

AF:

0.00104

AC:

AN:

4790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1188

East Asian (EAS)

AF:

0.00

AC:

AN:

2206

South Asian (SAS)

AF:

0.00

AC:

AN:

1646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

27368

Other (OTH)

AF:

0.00

AC:

AN:

730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000642

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.059

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.029

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0077

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.97

PhyloP100

0.26

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.56

REVEL

Benign

0.055

Sift

Benign

0.45

Sift4G

Benign

0.12

Polyphen

0.097

Vest4

0.40

MutPred

0.25

Gain of catalytic residue at C316 (P = 0.0085)

MVP

0.54

MPC

0.37

ClinPred

0.12

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.10

gMVP

0.086

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over