rs1553164387

Positions:

• chr1-16986288-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022089.4(ATP13A2):​c.3476T>C​(p.Phe1159Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP13A2 NM_022089.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

Genes affected

ATP13A2 (HGNC:30213): (ATPase cation transporting 13A2) This gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS), also referred to as Parkinson disease 9. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2008]

ATP13A2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.3476T>C	p.Phe1159Ser	missense_variant	29/29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.3476T>C	p.Phe1159Ser	missense_variant	29/29	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2017

This sequence change replaces phenylalanine with serine at codon 1159 of the ATP13A2 protein (p.Phe1159Ser). The phenylalanine residue is weakly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATP13A2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.53
MutPred		0.48		Gain of phosphorylation at F1159 (P = 0.0098);.;
MVP		0.70
MPC		1.4
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.66
gMVP		0.66

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

Other links and lift over

dbSNP: rs1553164387; hg19: chr1-17312783;