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GeneBe

rs754873504

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_004993.6(ATXN3):c.357C>G(p.His119Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000134 in 1,489,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

ATXN3
NM_004993.6 missense

Scores

8
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.09
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a active_site Proton acceptor (size 0) in uniprot entity ATX3_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATXN3NM_004993.6 linkuse as main transcriptc.357C>G p.His119Gln missense_variant 5/11 ENST00000644486.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATXN3ENST00000644486.2 linkuse as main transcriptc.357C>G p.His119Gln missense_variant 5/11 NM_004993.6 P1P54252-2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151970
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000128
AC:
3
AN:
234340
Hom.:
0
AF XY:
0.0000158
AC XY:
2
AN XY:
126950
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000279
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
7.48e-7
AC:
1
AN:
1337532
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
669916
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.90e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151970
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74218
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 27, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.31
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.68
D;T;.;D;.;.;.;.;T;.;D;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.43
D
MutationAssessor
Pathogenic
3.9
H;.;.;H;.;.;H;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.92
D
Polyphen
1.0
.;.;.;.;.;D;.;.;.;.;.;.
Vest4
0.85, 0.83, 0.83, 0.84, 0.90, 0.91, 0.84
MutPred
0.77
Gain of catalytic residue at W120 (P = 0.0107);.;Gain of catalytic residue at W120 (P = 0.0107);Gain of catalytic residue at W120 (P = 0.0107);.;.;Gain of catalytic residue at W120 (P = 0.0107);.;.;Gain of catalytic residue at W120 (P = 0.0107);Gain of catalytic residue at W120 (P = 0.0107);Gain of catalytic residue at W120 (P = 0.0107);
MVP
0.90
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.94
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754873504; hg19: chr14-92559626; API