Genetic Variant NM_198505.4:c.2737G>T (chr3-193301249-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_198505.4(ATP13A5):c.2737G>T(p.Gly913Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATP13A5
NM_198505.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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]

ATP13A5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A5	NM_198505.4 link	c.2737G>T	p.Gly913Cys	missense_variant	Exon 24 of 30	ENST00000342358.9	NP_940907.2	Q4VNC0
ATP13A5	XM_011512770.3 link	c.2737G>T	p.Gly913Cys	missense_variant	Exon 24 of 27		XP_011511072.1
ATP13A5	XM_047448075.1 link	c.1483G>T	p.Gly495Cys	missense_variant	Exon 14 of 20		XP_047304031.1
ATP13A5	XM_017006305.1 link	c.1060G>T	p.Gly354Cys	missense_variant	Exon 11 of 17		XP_016861794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A5	ENST00000342358.9 link	c.2737G>T	p.Gly913Cys	missense_variant	Exon 24 of 30	1	NM_198505.4	ENSP00000341942.4		Q4VNC0
ATP13A5	ENST00000495496.1 link	n.559G>T		non_coding_transcript_exon_variant	Exon 6 of 12	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461156

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.72

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.52

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.010

Polyphen

0.99

Vest4

0.67

MutPred

0.67

Loss of catalytic residue at G913 (P = 0.1524);

MVP

0.70

MPC

0.45

ClinPred

0.93

GERP RS

4.4

Varity_R

0.17

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over