3-194425519-T-C

Position:

• chr3-194425519-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001367549.1(ATP13A3):​c.3136A>G​(p.Thr1046Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,611,388 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: ATP13A3 NM_001367549.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.169

Genes affected

ATP13A3 (HGNC:24113): (ATPase 13A3) ATP13A3 is a member of the P-type ATPase family of proteins that transport a variety of cations across membranes. Other P-type ATPases include ATP7B (MIM 606882) and ATP7A (MIM 300011).[supplied by OMIM, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP13A3. . Gene score misZ 3.0145 (greater than the threshold 3.09). Trascript score misZ 3.7428 (greater than threshold 3.09). GenCC has associacion of gene with pulmonary arterial hypertension.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0039176047).
• BP6: Variant 3-194425519-T-C is Benign according to our data. Variant chr3-194425519-T-C is described in ClinVar as [Benign]. Clinvar id is 1670948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00156 (237/152358) while in subpopulation NFE AF= 0.00171 (116/68032). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A3	NM_001367549.1	c.3136A>G	p.Thr1046Ala	missense_variant	30/34	ENST00000645319.2	NP_001354478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A3	ENST00000645319.2	c.3136A>G	p.Thr1046Ala	missense_variant	30/34		NM_001367549.1	ENSP00000494937

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00170

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00195 AC: 480 AN: 246138 Hom.: 0 AF XY: 0.00205 AC XY: 274 AN XY: 133502

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000595

Gnomad ASJ exome AF: 0.00789

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000711

Gnomad FIN exome AF: 0.00544

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00172 AC: 2504 AN: 1459030 Hom.: 4 Cov.: 31 AF XY: 0.00171 AC XY: 1239 AN XY: 725696

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000612

Gnomad4 ASJ exome AF: 0.00675

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000808

Gnomad4 FIN exome AF: 0.00590

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74506

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00668

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00187 Hom.: 1

Bravo AF: 0.00111

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000275 AC: 1

ESP6500EA AF: 0.00171 AC: 14

ExAC AF: 0.00200 AC: 242

EpiCase AF: 0.00224

EpiControl AF: 0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ATP13A3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	10
DANN	Benign	0.47
DEOGEN2	Benign	0.26	T;T;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.54	.;.;T;T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.0039	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.76	N;N;.;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.060	N;.;.;N;.
REVEL	Benign	0.22
Sift	Benign	0.83	T;.;.;T;.
Sift4G	Benign	0.86	T;.;.;T;.
Polyphen		0.0	B;B;.;B;.
Vest4		0.078
MVP		0.41
MPC		0.35
ClinPred		0.0018	T
GERP RS		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.35

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: rs189073215; hg19: chr3-194146248;