3-193275056-A-G

Variant names:

• chr3-193275056-A-G
• NM_198505.4:c.3643T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198505.4(ATP13A5):​c.3643T>C​(p.Trp1215Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP13A5 NM_198505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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]

PLAAT1 (HGNC:14922): (phospholipase A and acyltransferase 1) Enables acyltransferase activity, transferring groups other than amino-acyl groups and phospholipase activity. Involved in N-acylphosphatidylethanolamine metabolic process and phosphatidylcholine metabolic process. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A5	NM_198505.4	c.3643T>C	p.Trp1215Arg	missense_variant	Exon 30 of 30	ENST00000342358.9	NP_940907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A5	ENST00000342358.9	c.3643T>C	p.Trp1215Arg	missense_variant	Exon 30 of 30	1	NM_198505.4	ENSP00000341942.4
ATP13A5	ENST00000495496.1	n.1465T>C		non_coding_transcript_exon_variant	Exon 12 of 12	5
PLAAT1	ENST00000416012.1	n.*60-2580A>G		intron_variant	Intron 2 of 2	5		ENSP00000414431.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3643T>C (p.W1215R) alteration is located in exon 30 (coding exon 30) of the ATP13A5 gene. This alteration results from a T to C substitution at nucleotide position 3643, causing the tryptophan (W) at amino acid position 1215 to be replaced by an arginine (R). 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	0.21
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0059	T;.
Eigen	Benign	0.098
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.80	P;.
Vest4		0.49
MutPred		0.44		Gain of disorder (P = 0.0037);.;
MVP		0.61
MPC		0.40
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.40
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-192992845;