3-193402704-C-T

Variant names:

• chr3-193402704-C-T
• NM_032279.4:c.3539G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032279.4(ATP13A4):​c.3539G>A​(p.Arg1180Lys) 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 benign outcome for this variant. 16/21 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)
• Consequence: ATP13A4 NM_032279.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.228

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027971208).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A4	NM_032279.4	c.3539G>A	p.Arg1180Lys	missense_variant	Exon 30 of 30	ENST00000342695.9	NP_115655.2
ATP13A4	XM_047449063.1	c.3668G>A	p.Arg1223Lys	missense_variant	Exon 32 of 32		XP_047305019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A4	ENST00000342695.9	c.3539G>A	p.Arg1180Lys	missense_variant	Exon 30 of 30	1	NM_032279.4	ENSP00000339182.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3539G>A (p.R1180K) alteration is located in exon 30 (coding exon 30) of the ATP13A4 gene. This alteration results from a G to A substitution at nucleotide position 3539, causing the arginine (R) at amino acid position 1180 to be replaced by a lysine (K). 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	0.066
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.29
DANN	Benign	0.33
DEOGEN2	Benign	0.0025	.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.55	.;.;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.54	N;N;N
REVEL	Benign	0.084
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.80	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.10
MutPred		0.20		.;.;Gain of ubiquitination at R1180 (P = 0.001);
MVP		0.26
MPC		0.12
ClinPred		0.028	T
GERP RS		-0.019
Varity_R		0.039
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-193120493;