3-193279410-A-G

Position:

• chr3-193279410-A-G

Variant summary

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

The NM_198505.4(ATP13A5):​c.3271T>C​(p.Phe1091Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP13A5 NM_198505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

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]

ATP13A5 (HGNC:):

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/exons	MANE	Protein	UniProt
ATP13A5	NM_198505.4	c.3271T>C	p.Phe1091Leu	missense_variant	28/30	ENST00000342358.9	NP_940907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A5	ENST00000342358.9	c.3271T>C	p.Phe1091Leu	missense_variant	28/30	1	NM_198505.4	ENSP00000341942.4
ATP13A5	ENST00000495496.1	n.1093T>C		non_coding_transcript_exon_variant	10/12	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.3271T>C (p.F1091L) alteration is located in exon 28 (coding exon 28) of the ATP13A5 gene. This alteration results from a T to C substitution at nucleotide position 3271, causing the phenylalanine (F) at amino acid position 1091 to be replaced by a leucine (L). 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	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.50
Sift	Benign	0.11	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.47		Gain of helix (P = 0.062);
MVP		0.59
MPC		0.45
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.39
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr3-192997199;