Genetic Variant ATP13A3:p.Pro1203Leu (chr3-194406082-G-A) – 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_001367549.1(ATP13A3):c.3608C>T(p.Pro1203Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1203R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATP13A3
NM_001367549.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.72

Publications

0 publications found

Variant links:

Genes affected

ATP13A3 (HGNC:24113): (ATPase 13A3) ATP13A3 is a member of the P-type ATPase family of proteins that transport a variety of cations across membranes. Other P-type ATPases include ATP7B (MIM 606882) and ATP7A (MIM 300011).[supplied by OMIM, Aug 2008]

ATP13A3 Gene-Disease associations (from GenCC):

pulmonary arterial hypertension
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen

ATP13A3 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=0.24806958).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367549.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP13A3	NM_001367549.1	MANE Select	c.3608C>T	p.Pro1203Leu	missense	Exon 34 of 34	NP_001354478.1	A0A2R8Y635
ATP13A3	NM_001374836.1		c.3527C>T	p.Pro1176Leu	missense	Exon 33 of 33	NP_001361765.1
ATP13A3	NM_001437993.1		c.3518C>T	p.Pro1173Leu	missense	Exon 33 of 33	NP_001424922.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP13A3	ENST00000645319.2	MANE Select	c.3608C>T	p.Pro1203Leu	missense	Exon 34 of 34	ENSP00000494937.2	A0A2R8Y635
ATP13A3	ENST00000429136.7	TSL:1	n.1454C>T		non_coding_transcript_exon	Exon 13 of 13
ATP13A3	ENST00000461660.2	TSL:1	n.712C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.015

Eigen

Benign

-0.041

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.84

M_CAP

Benign

0.0085

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

8.7

PrimateAI

Benign

0.35

PROVEAN

Benign

0.61

REVEL

Benign

0.12

Sift

Benign

0.79

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.15

MutPred

0.49

Loss of loop (P = 0.0288)

MVP

0.043

MPC

0.37

ClinPred

0.97

GERP RS

5.8

Varity_R

0.12

gMVP

0.41

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over