1-16986101-T-A

Position:

chr1-16986101-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000341676.9(ATP13A2):c.3361A>T(p.Thr1121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,555,544 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0055 ( 18 hom. )

Consequence

ATP13A2
ENST00000341676.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.390

Variant links:

Genes affected

ATP13A2 (HGNC:30213): (ATPase cation transporting 13A2) This gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS), also referred to as Parkinson disease 9. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2008]

ATP13A2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053931773).

BP6

Variant 1-16986101-T-A is Benign according to our data. Variant chr1-16986101-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 493023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16986101-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00405 (590/145580) while in subpopulation NFE AF= 0.00626 (413/66022). AF 95% confidence interval is 0.00576. There are 6 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP13A2	NM_022089.4 linkuse as main transcript	c.*120A>T		3_prime_UTR_variant	29/29	ENST00000326735.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP13A2	ENST00000326735.13 linkuse as main transcript	c.*120A>T		3_prime_UTR_variant	29/29	1	NM_022089.4	A1	Q9NQ11-1
	ENST00000446261.1 linkuse as main transcript	n.187+6989T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00406

AC:

590

AN:

145466

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00572

Gnomad ASJ

AF:

0.00382

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00219

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.00625

Gnomad OTH

AF:

0.00545

GnomAD3 exomes

AF:

0.00350

AC:

615

AN:

175576

Hom.:

AF XY:

0.00323

AC XY:

304

AN XY:

94146

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00331

Gnomad ASJ exome

AF:

0.00162

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00278

Gnomad NFE exome

AF:

0.00579

Gnomad OTH exome

AF:

0.00566

GnomAD4 exome

AF:

0.00547

AC:

7708

AN:

1409964

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

3690

AN XY:

696420

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00388

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000752

Gnomad4 FIN exome

AF:

0.00309

Gnomad4 NFE exome

AF:

0.00648

Gnomad4 OTH exome

AF:

0.00479

GnomAD4 genome

AF:

0.00405

AC:

590

AN:

145580

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

269

AN XY:

70882

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00571

Gnomad4 ASJ

AF:

0.00382

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00219

Gnomad4 NFE

AF:

0.00626

Gnomad4 OTH

AF:

0.00539

Alfa

AF:

0.00513

Hom.:

Bravo

AF:

0.00428

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00440

AC:

ExAC

AF:

0.00285

AC:

338

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ATP13A2: PP3, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Kufor-Rakeb syndrome

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

ATP13A2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

0.48

DANN

Benign

0.90

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.31

T;T

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.30

MutationTaster

Benign

0.51

D;D;N

PROVEAN

Benign

-0.41

N;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.67

.;T

Vest4

0.17

MutPred

0.10

Loss of sheet (P = 0.1158);.;

MVP

0.42

ClinPred

0.018

GERP RS

-0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over