19-19645706-G-A

Position:

• chr19-19645706-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_020410.3(ATP13A1):​c.3445C>T​(p.Leu1149Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000348 in 1,436,196 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: ATP13A1 NM_020410.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.10

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747
• BS2: High AC in GnomAdExome4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A1	NM_020410.3	c.3445C>T	p.Leu1149Phe	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.3445C>T	p.Leu1149Phe	missense_variant	25/26	1	NM_020410.3	ENSP00000349877.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000348 AC: 50 AN: 1436196 Hom.: 0 Cov.: 31 AF XY: 0.0000267 AC XY: 19 AN XY: 712152

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: 0.0000455

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000827 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

Dec 27, 2023

The c.3445C>T (p.L1149F) alteration is located in exon 25 (coding exon 25) of the ATP13A1 gene. This alteration results from a C to T substitution at nucleotide position 3445, causing the leucine (L) at amino acid position 1149 to be replaced by a phenylalanine (F). 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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.98	D;D
Vest4		0.73
MutPred		0.44		.;Loss of helix (P = 0.079);
MVP		0.71
MPC		1.1
ClinPred		0.84	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.72

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: rs749189208; hg19: chr19-19756515;