Genetic Variant NM_004993.6:c.891A>C (chr14-92071035-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004993.6(ATXN3):c.891A>C(p.Gln297His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 537,314 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q297Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

ATXN3
NM_004993.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.273

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:

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ACMG classification

Classification was made for transcript

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=0.08118275).

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.891A>C	p.Gln297His	missense	Exon 10 of 11	NP_004984.2
ATXN3	NM_001127696.2		c.846A>C	p.Gln282His	missense	Exon 9 of 10	NP_001121168.1	P54252-4
ATXN3	NM_001127697.3		c.738A>C	p.Gln246His	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.891A>C	p.Gln297His	missense	Exon 10 of 11	ENSP00000496695.1	P54252-2
ATXN3	ENST00000532032.5	TSL:1	c.891A>C	p.Gln297His	missense	Exon 10 of 10	ENSP00000437157.1	P54252-1
ATXN3	ENST00000503767.5	TSL:1	c.846A>C	p.Gln282His	missense	Exon 9 of 10	ENSP00000426697.1	P54252-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000186

AC:

AN:

537314

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

270022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15048

American (AMR)

AF:

0.00

AC:

AN:

16450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9786

East Asian (EAS)

AF:

0.00

AC:

AN:

22186

South Asian (SAS)

AF:

0.00

AC:

AN:

45748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1880

European-Non Finnish (NFE)

AF:

0.00000260

AC:

AN:

385288

Other (OTH)

AF:

0.00

AC:

AN:

22726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

6.5

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.065

Eigen

Benign

-0.91

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.82

M_CAP

Benign

0.0033

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.92

PhyloP100

-0.27

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.0

REVEL

Benign

0.13

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.011

Polyphen

0.71

Vest4

0.49

MutPred

0.16

Loss of MoRF binding (P = 0.1302)

MVP

0.59

MPC

0.21

ClinPred

0.12

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.47

gMVP

0.099

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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