3-193412265-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_032279.4(ATP13A4):​c.3121G>A​(p.Val1041Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,613,472 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

ATP13A4
NM_032279.4 missense

Scores

19

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.294
Variant links:
Genes affected
ATP13A4 (HGNC:25422): (ATPase 13A4) Predicted to enable ATPase-coupled cation transmembrane transporter activity. Predicted to be involved in cellular calcium ion homeostasis. Predicted to be located in endoplasmic reticulum membrane and endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0091436505).
BP6
Variant 3-193412265-C-T is Benign according to our data. Variant chr3-193412265-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 729133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP13A4NM_032279.4 linkc.3121G>A p.Val1041Ile missense_variant Exon 27 of 30 ENST00000342695.9 NP_115655.2 Q4VNC1-1B3KU47
ATP13A4XM_047449063.1 linkc.3250G>A p.Val1084Ile missense_variant Exon 29 of 32 XP_047305019.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP13A4ENST00000342695.9 linkc.3121G>A p.Val1041Ile missense_variant Exon 27 of 30 1 NM_032279.4 ENSP00000339182.4 Q4VNC1-1

Frequencies

GnomAD3 genomes
AF:
0.000657
AC:
100
AN:
152162
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00232
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.000147
AC:
37
AN:
251470
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00191
Gnomad AMR exome
AF:
0.000173
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000568
AC:
83
AN:
1461192
Hom.:
0
Cov.:
31
AF XY:
0.0000536
AC XY:
39
AN XY:
726950
show subpopulations
Gnomad4 AFR exome
AF:
0.00200
Gnomad4 AMR exome
AF:
0.000179
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000657
AC:
100
AN:
152280
Hom.:
1
Cov.:
32
AF XY:
0.000672
AC XY:
50
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.00231
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000948
Alfa
AF:
0.000129
Hom.:
0
Bravo
AF:
0.000752
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000140
AC:
17

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Dec 14, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ATP13A4-related disorder Benign:1
Jun 12, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

not provided Benign:1
Dec 13, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.053
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
8.4
DANN
Benign
0.52
DEOGEN2
Benign
0.0089
.;T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.0043
N
LIST_S2
Benign
0.075
T;T;T
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.0091
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.035
.;.;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.28
N;N;N
REVEL
Benign
0.033
Sift
Benign
0.74
T;T;T
Sift4G
Benign
0.79
T;T;T
Polyphen
0.0
.;.;B
Vest4
0.13
MVP
0.28
MPC
0.092
ClinPred
0.010
T
GERP RS
0.51
Varity_R
0.020
gMVP
0.12

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.

Other links and lift over

dbSNP: rs115558454; hg19: chr3-193130054; API