3-193334980-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_198505.4(ATP13A5):c.1063C>T(p.Gln355*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,613,820 control chromosomes in the GnomAD database, including 863 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.023 ( 42 hom., cov: 32)

Exomes 𝑓: 0.030 ( 821 hom. )

Consequence

ATP13A5
NM_198505.4 stop_gained

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 9.68

Publications

16 publications found

Variant links:

Genes affected

ATP13A5 (HGNC:31789): (ATPase 13A5) This gene encodes a member of the P5 subfamily of P-type transport ATPases. P-type ATPases form a large superfamily of cation and lipid pumps that transport inorganic cations and other substrates across cell membranes. P5 ATPases are localized to membranes of the endoplasmic reticulum (ER) and serve many important functions including transport of cargo proteins to the Golgi, glycosylation and cell wall biosynthesis, control of protein insertion orientation, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) degradation, and sensitivity to unfolded protein response (UPR) activators. The encoded protein is organized into three cytoplasmic domains (A, P, and N) and two membrane-embedded domains (T and S). The N-domain binds ATP and serves as a built-in protein kinase, which phosphorylates the P-domain. The A-domain is an intrinsic protein phosphatase, which dephosphorylates the P-domain once during each catalytic cycle. [provided by RefSeq, Jul 2017]

ATP13A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 3-193334980-G-A is Benign according to our data. Variant chr3-193334980-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 402400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0231 (3512/152282) while in subpopulation NFE AF = 0.0337 (2291/68016). AF 95% confidence interval is 0.0325. There are 42 homozygotes in GnomAd4. There are 1750 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A5	NM_198505.4 link	c.1063C>T	p.Gln355*	stop_gained	Exon 10 of 30	ENST00000342358.9	NP_940907.2	Q4VNC0
ATP13A5	XM_011512770.3 link	c.1063C>T	p.Gln355*	stop_gained	Exon 10 of 27		XP_011511072.1
ATP13A5	XM_047448075.1 link	c.19-3669C>T		intron_variant	Intron 1 of 19		XP_047304031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A5	ENST00000342358.9 link	c.1063C>T	p.Gln355*	stop_gained	Exon 10 of 30	1	NM_198505.4	ENSP00000341942.4		Q4VNC0

Frequencies

GnomAD3 genomes

AF:

0.0231

AC:

3512

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00557

Gnomad AMI

AF:

0.0527

Gnomad AMR

AF:

0.0206

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0498

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0337

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0220

AC:

5520

AN:

251162

AF XY:

0.0219

show subpopulations

Gnomad AFR exome

AF:

0.00499

Gnomad AMR exome

AF:

0.00926

Gnomad ASJ exome

AF:

0.00784

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0491

Gnomad NFE exome

AF:

0.0322

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.0299

AC:

43716

AN:

1461538

Hom.:

821

Cov.:

AF XY:

0.0291

AC XY:

21166

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.00514

AC:

172

AN:

33462

American (AMR)

AF:

0.00859

AC:

384

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00834

AC:

218

AN:

26124

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.00665

AC:

573

AN:

86210

European-Finnish (FIN)

AF:

0.0480

AC:

2564

AN:

53418

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0343

AC:

38164

AN:

1111772

Other (OTH)

AF:

0.0267

AC:

1614

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2156

4313

6469

8626

10782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1396

2792

4188

5584

6980

<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:

0.0231

AC:

3512

AN:

152282

Hom.:

Cov.:

AF XY:

0.0235

AC XY:

1750

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00556

AC:

231

AN:

41570

American (AMR)

AF:

0.0205

AC:

314

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00560

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0498

AC:

529

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0337

AC:

2291

AN:

68016

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

180

360

541

721

901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0282

Hom.:

231

Bravo

AF:

0.0201

TwinsUK

AF:

0.0418

AC:

155

ALSPAC

AF:

0.0361

AC:

139

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0298

AC:

256

ExAC

AF:

0.0217

AC:

2633

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0307

EpiControl

AF:

0.0282

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.7

Vest4

0.35

GERP RS

5.9

Mutation Taster

=43/157

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over