3-193301249-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198505.4(ATP13A5):​c.2737G>A​(p.Gly913Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,220 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

ATP13A5
NM_198505.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.025984257).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP13A5NM_198505.4 linkuse as main transcriptc.2737G>A p.Gly913Ser missense_variant 24/30 ENST00000342358.9 NP_940907.2 Q4VNC0
ATP13A5XM_011512770.3 linkuse as main transcriptc.2737G>A p.Gly913Ser missense_variant 24/27 XP_011511072.1
ATP13A5XM_047448075.1 linkuse as main transcriptc.1483G>A p.Gly495Ser missense_variant 14/20 XP_047304031.1
ATP13A5XM_017006305.1 linkuse as main transcriptc.1060G>A p.Gly354Ser missense_variant 11/17 XP_016861794.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP13A5ENST00000342358.9 linkuse as main transcriptc.2737G>A p.Gly913Ser missense_variant 24/301 NM_198505.4 ENSP00000341942.4 Q4VNC0
ATP13A5ENST00000495496.1 linkuse as main transcriptn.559G>A non_coding_transcript_exon_variant 6/125

Frequencies

GnomAD3 genomes
AF:
0.000132
AC:
20
AN:
152064
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000200
AC:
50
AN:
250538
Hom.:
0
AF XY:
0.000192
AC XY:
26
AN XY:
135400
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00129
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000301
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000157
AC:
229
AN:
1461156
Hom.:
0
Cov.:
30
AF XY:
0.000160
AC XY:
116
AN XY:
726872
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00161
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.000156
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000132
AC:
20
AN:
152064
Hom.:
0
Cov.:
33
AF XY:
0.0000942
AC XY:
7
AN XY:
74272
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000295
Hom.:
1
Bravo
AF:
0.000121
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000157
AC:
19
EpiCase
AF:
0.000546
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 31, 2022The c.2737G>A (p.G913S) alteration is located in exon 24 (coding exon 24) of the ATP13A5 gene. This alteration results from a G to A substitution at nucleotide position 2737, causing the glycine (G) at amino acid position 913 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
16
DANN
Benign
0.092
DEOGEN2
Benign
0.029
T
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.57
T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.026
T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
-0.12
N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
1.7
N
REVEL
Benign
0.19
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0090
B
Vest4
0.37
MVP
0.32
MPC
0.11
ClinPred
0.046
T
GERP RS
4.4
Varity_R
0.026
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs200528703; hg19: chr3-193019038; COSMIC: COSV60875736; API