3-194419935-T-A

Position:

chr3-194419935-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_001367549.1(ATP13A3):c.3346A>T(p.Ile1116Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000885 in 1,536,090 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000091 ( 1 hom. )

Consequence

ATP13A3
NM_001367549.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.225

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 links:

ATP13A3 (HGNC:):

ATP13A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP13A3. . Gene score misZ 3.0145 (greater than the threshold 3.09). Trascript score misZ 3.7428 (greater than threshold 3.09). GenCC has associacion of gene with pulmonary arterial hypertension.

BP4

Computational evidence support a benign effect (MetaRNN=0.06294325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A3	NM_001367549.1 linkuse as main transcript	c.3346A>T	p.Ile1116Phe	missense_variant	31/34	ENST00000645319.2	NP_001354478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A3	ENST00000645319.2 linkuse as main transcript	c.3346A>T	p.Ile1116Phe	missense_variant	31/34		NM_001367549.1	ENSP00000494937.2		A0A2R8Y635

Frequencies

GnomAD3 genomes

AF:

0.0000659

AC:

AN:

151722

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000538

AC:

AN:

185866

Hom.:

AF XY:

0.0000578

AC XY:

AN XY:

103768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000556

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000992

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000910

AC:

126

AN:

1384250

Hom.:

Cov.:

AF XY:

0.0000857

AC XY:

AN XY:

688268

show subpopulations

Gnomad4 AFR exome

AF:

0.000105

Gnomad4 AMR exome

AF:

0.0000371

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.0000354

GnomAD4 genome

AF:

0.0000659

AC:

AN:

151840

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000263

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000748

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ATP13A3-related conditions. This variant is present in population databases (rs200180433, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces isoleucine with phenylalanine at codon 1116 of the ATP13A3 protein (p.Ile1116Phe). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

3.5

DANN

Benign

0.81

DEOGEN2

Benign

0.37

T;T;.;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.25

.;.;T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.063

T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.97

L;L;.;L

MutationTaster

Benign

0.61

D;D

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.66

N;.;.;N

REVEL

Benign

0.13

Sift

Benign

0.65

T;.;.;T

Sift4G

Benign

0.081

T;.;.;T

Polyphen

0.0

B;B;.;B

Vest4

0.095

MVP

0.40

MPC

0.57

ClinPred

0.042

GERP RS

2.8

Varity_R

0.023

gMVP

0.60

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

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