19-19645656-G-C

Position:

• chr19-19645656-G-C

Variant summary

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

The NM_020410.3(ATP13A1):​c.3495C>G​(p.Ile1165Met) 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: ATP13A1 NM_020410.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

Genes affected

ATP13A1 (HGNC:24215): (ATPase 13A1) Enables transmembrane protein dislocase activity. Involved in extraction of mislocalized protein from ER membrane. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATP13A1 (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
ATP13A1	NM_020410.3	c.3495C>G	p.Ile1165Met	missense_variant	25/26	ENST00000357324.11	NP_065143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A1	ENST00000357324.11	c.3495C>G	p.Ile1165Met	missense_variant	25/26	1	NM_020410.3	ENSP00000349877.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000837 AC: 1

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

Jan 26, 2023

The c.3495C>G (p.I1165M) alteration is located in exon 25 (coding exon 25) of the ATP13A1 gene. This alteration results from a C to G substitution at nucleotide position 3495, causing the isoleucine (I) at amino acid position 1165 to be replaced by a methionine (M). 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	0.23
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	.;T
Eigen	Benign	-0.095
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.85	.;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.27	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.57	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.097	B;B
Vest4		0.85
MutPred		0.57		.;Loss of stability (P = 0.0711);
MVP		0.87
MPC		1.1
ClinPred		0.47	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748523704; hg19: chr19-19756465;