chr3-193289944-C-G

Position:

chr3-193289944-C-G

Variant summary

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

The NM_198505.4(ATP13A5):c.2964G>C(p.Gln988His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00008 in 1,612,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

ATP13A5
NM_198505.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0330

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]

ATP13A5 links:

ATP13A5 (HGNC:):

ATP13A5 links:

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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=0.030752152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A5	NM_198505.4 linkuse as main transcript	c.2964G>C	p.Gln988His	missense_variant	26/30	ENST00000342358.9	NP_940907.2	Q4VNC0
ATP13A5	XM_047448075.1 linkuse as main transcript	c.1710G>C	p.Gln570His	missense_variant	16/20		XP_047304031.1
ATP13A5	XM_017006305.1 linkuse as main transcript	c.1287G>C	p.Gln429His	missense_variant	13/17		XP_016861794.1
ATP13A5	XM_011512770.3 linkuse as main transcript	c.2849-1G>C		splice_acceptor_variant, intron_variant			XP_011511072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A5	ENST00000342358.9 linkuse as main transcript	c.2964G>C	p.Gln988His	missense_variant	26/30	1	NM_198505.4	ENSP00000341942.4		Q4VNC0
ATP13A5	ENST00000495496.1 linkuse as main transcript	n.786G>C		non_coding_transcript_exon_variant	8/12	5

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000116

AC:

AN:

250364

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135324

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.0000873

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:

0.000164

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1460572

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726612

show subpopulations

Gnomad4 AFR exome

AF:

0.00141

Gnomad4 AMR exome

AF:

0.0000673

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:

0.00000630

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000401

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000442

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

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 submitter

clinical testing

Ambry Genetics

Aug 02, 2023

The c.2964G>C (p.Q988H) alteration is located in exon 26 (coding exon 26) of the ATP13A5 gene. This alteration results from a G to C substitution at nucleotide position 2964, causing the glutamine (Q) at amino acid position 988 to be replaced by a histidine (H). 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

Uncertain

0.45

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.45

DEOGEN2

Benign

0.24

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.60

M_CAP

Benign

0.041

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.30

Sift

Benign

0.22

Sift4G

Benign

0.084

Polyphen

0.0030

Vest4

0.47

MutPred

0.53

Loss of helix (P = 0.0626);

MVP

0.14

MPC

0.37

ClinPred

0.023

GERP RS

-2.9

Varity_R

0.075

gMVP

0.78

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