3-193402777-T-C

Position:

• chr3-193402777-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000342695.9(ATP13A4):​c.3466A>G​(p.Arg1156Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ATP13A4 ENST00000342695.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

Genes affected

ATP13A4 (HGNC:25422): (ATPase 13A4) Predicted to enable ATPase-coupled cation transmembrane transporter activity. Predicted to be involved in cellular calcium ion homeostasis. Predicted to be located in endoplasmic reticulum membrane and endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2664515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A4	NM_032279.4	c.3466A>G	p.Arg1156Gly	missense_variant	30/30	ENST00000342695.9	NP_115655.2
ATP13A4	XM_047449063.1	c.3595A>G	p.Arg1199Gly	missense_variant	32/32		XP_047305019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A4	ENST00000342695.9	c.3466A>G	p.Arg1156Gly	missense_variant	30/30	1	NM_032279.4	ENSP00000339182	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461764 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727198

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: 0.0000375

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

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 19, 2023

The c.3466A>G (p.R1156G) alteration is located in exon 30 (coding exon 30) of the ATP13A4 gene. This alteration results from a A to G substitution at nucleotide position 3466, causing the arginine (R) at amino acid position 1156 to be replaced by a glycine (G). 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	0.18
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	.;T;T
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	.;.;M
MutationTaster	Benign	0.86	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.64	.;.;P
Vest4		0.49
MVP		0.50
MPC		0.15
ClinPred		0.21	T
GERP RS		2.5
Varity_R		0.31
gMVP		0.52

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: rs771987417; hg19: chr3-193120566; COSMIC: COSV61321398;