rs6788448

chr3-193491389-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032279.4(ATP13A4):c.543A>G(p.Ile181Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,581,422 control chromosomes in the GnomAD database, including 135,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.44 (14831 hom., cov: 32)
  • Exomes 𝑓: 0.41 (120481 hom.)
• Consequence: ATP13A4 NM_032279.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.414

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.139776E-4).
• BP6: Variant 3-193491389-T-C is Benign according to our data. Variant chr3-193491389-T-C is described in ClinVar as [Benign]. Clinvar id is 1229084.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP13A4	NM_032279.4	c.543A>G	p.Ile181Met	missense_variant	6/30	ENST00000342695.9
ATP13A4	XM_047449063.1	c.672A>G	p.Ile224Met	missense_variant	8/32
ATP13A4	XM_017007319.2	c.672A>G	p.Ile224Met	missense_variant	8/27
ATP13A4	XR_007095757.1	n.936A>G		non_coding_transcript_exon_variant	8/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP13A4	ENST00000342695.9	c.543A>G	p.Ile181Met	missense_variant	6/30	1	NM_032279.4	P1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66755 AN: 151896 Hom.: 14813 Cov.: 32

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.431

GnomAD3 exomes AF: 0.428 AC: 107402 AN: 250688 Hom.: 23521 AF XY: 0.424 AC XY: 57527 AN XY: 135556

Gnomad AFR exome AF: 0.512

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.443

Gnomad SAS exome AF: 0.449

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.431

GnomAD4 exome AF: 0.408 AC: 582961 AN: 1429408 Hom.: 120481 Cov.: 30 AF XY: 0.408 AC XY: 291041 AN XY: 712910

Gnomad4 AFR exome AF: 0.514

Gnomad4 AMR exome AF: 0.519

Gnomad4 ASJ exome AF: 0.369

Gnomad4 EAS exome AF: 0.412

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.347

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.413

GnomAD4 genome AF: 0.440 AC: 66815 AN: 152014 Hom.: 14831 Cov.: 32 AF XY: 0.438 AC XY: 32534 AN XY: 74312

Gnomad4 AFR AF: 0.509

Gnomad4 AMR AF: 0.486

Gnomad4 ASJ AF: 0.367

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.349

Gnomad4 NFE AF: 0.404

Gnomad4 OTH AF: 0.427

Alfa AF: 0.412 Hom.: 33774

Bravo AF: 0.452

TwinsUK AF: 0.413 AC: 1532

ALSPAC AF: 0.405 AC: 1562

ESP6500AA AF: 0.515 AC: 2270

ESP6500EA AF: 0.404 AC: 3476

ExAC AF: 0.427 AC: 51820

Asia WGS AF: 0.459 AC: 1596 AN: 3474

EpiCase AF: 0.409

EpiControl AF: 0.405

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.029	T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.00091	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.11	P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.099
MPC		0.55
ClinPred		0.038	T
GERP RS		4.6
Varity_R		0.29
gMVP		0.78

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: rs6788448; hg19: chr3-193209178; COSMIC: COSV55066065;