Genetic Variant ATXN3L:p.Gly332Asp (chrX-13318940-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001135995.2(ATXN3L):c.995G>A(p.Gly332Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,208,315 control chromosomes in the GnomAD database, including 76,102 homozygotes. There are 160,490 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.51 ( 11769 hom., 16734 hem., cov: 23)

Exomes 𝑓: 0.39 ( 64333 hom. 143756 hem. )

Consequence

ATXN3L
NM_001135995.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.153

Publications

22 publications found

Variant links:

Genes affected

ATXN3L (HGNC:24173): (ataxin 3 like) This intronless gene may be a pseudogene (PMID:11450850). This gene is similar to the multi-exon gene which encodes ataxin 3 and contains a coding region which could encode a protein similar to ataxin 3. Mutations in the gene encoding ataxin 3 are associated with Machado-Joseph disease. [provided by RefSeq, Sep 2011]

ATXN3L links:

GS1-600G8.3 (HGNC:):

GS1-600G8.3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0593325E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3L	NM_001135995.2 link	c.995G>A	p.Gly332Asp	missense_variant	Exon 1 of 1	ENST00000380622.5	NP_001129467.1	Q9H3M9B4DYC7
ATXN3L	NM_001387036.1 link	c.731G>A	p.Gly244Asp	missense_variant	Exon 2 of 2		NP_001373965.1
GS1-600G8.3	NR_046087.1 link	n.1449-68C>T		intron_variant	Intron 15 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3L	ENST00000380622.5 link	c.995G>A	p.Gly332Asp	missense_variant	Exon 1 of 1	6	NM_001135995.2	ENSP00000369996.2		Q9H3M9
GS1-600G8.3	ENST00000431486.1 link	n.1449-68C>T		intron_variant	Intron 15 of 16	1

Frequencies

GnomAD3 genomes

AF:

0.508

AC:

56172

AN:

110634

Hom.:

11751

Cov.:

show subpopulations

Gnomad AFR

AF:

0.767

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.648

Gnomad ASJ

AF:

0.344

Gnomad EAS

AF:

0.836

Gnomad SAS

AF:

0.536

Gnomad FIN

AF:

0.362

Gnomad MID

AF:

0.369

Gnomad NFE

AF:

0.336

Gnomad OTH

AF:

0.513

GnomAD2 exomes

AF:

0.495

AC:

89477

AN:

180865

AF XY:

0.471

show subpopulations

Gnomad AFR exome

AF:

0.775

Gnomad AMR exome

AF:

0.775

Gnomad ASJ exome

AF:

0.349

Gnomad EAS exome

AF:

0.824

Gnomad FIN exome

AF:

0.363

Gnomad NFE exome

AF:

0.333

Gnomad OTH exome

AF:

0.448

GnomAD4 exome

AF:

0.395

AC:

433297

AN:

1097631

Hom.:

64333

Cov.:

AF XY:

0.396

AC XY:

143756

AN XY:

363233

show subpopulations

African (AFR)

AF:

0.777

AC:

20502

AN:

26390

American (AMR)

AF:

0.763

AC:

26862

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.346

AC:

6704

AN:

19380

East Asian (EAS)

AF:

0.861

AC:

26007

AN:

30202

South Asian (SAS)

AF:

0.539

AC:

29190

AN:

54121

European-Finnish (FIN)

AF:

0.360

AC:

14594

AN:

40496

Middle Eastern (MID)

AF:

0.390

AC:

1613

AN:

4133

European-Non Finnish (NFE)

AF:

0.342

AC:

288256

AN:

841660

Other (OTH)

AF:

0.425

AC:

19569

AN:

46052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

9373

18745

28118

37490

46863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10708

21416

32124

42832

53540

<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:

0.508

AC:

56244

AN:

110684

Hom.:

11769

Cov.:

AF XY:

0.508

AC XY:

16734

AN XY:

32912

show subpopulations

African (AFR)

AF:

0.768

AC:

23367

AN:

30442

American (AMR)

AF:

0.649

AC:

6769

AN:

10433

Ashkenazi Jewish (ASJ)

AF:

0.344

AC:

908

AN:

2636

East Asian (EAS)

AF:

0.836

AC:

2937

AN:

3513

South Asian (SAS)

AF:

0.537

AC:

1389

AN:

2589

European-Finnish (FIN)

AF:

0.362

AC:

2100

AN:

5809

Middle Eastern (MID)

AF:

0.363

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.336

AC:

17756

AN:

52863

Other (OTH)

AF:

0.520

AC:

783

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

837

1674

2510

3347

4184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.401

Hom.:

36280

Bravo

AF:

0.547

TwinsUK

AF:

0.351

AC:

1303

ALSPAC

AF:

0.345

AC:

998

ESP6500AA

AF:

0.762

AC:

2003

ESP6500EA

AF:

0.339

AC:

1862

ExAC

AF:

0.478

AC:

57598

EpiCase

AF:

0.331

EpiControl

AF:

0.340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-1.0

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.81

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.0038

FATHMM_MKL

Benign

0.000030

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0000011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.15

PrimateAI

Benign

0.35

PROVEAN

Benign

1.8

REVEL

Benign

0.19

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.011

MPC

0.094

ClinPred

0.0017

GERP RS

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.0099

Mutation Taster

=97/3

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over