3-193514750-T-C

Position:

• chr3-193514750-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032279.4(ATP13A4):​c.182A>G​(p.His61Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,614,170 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (15 hom.)
• Consequence: ATP13A4 NM_032279.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.61

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0104293525).
• BP6: Variant 3-193514750-T-C is Benign according to our data. Variant chr3-193514750-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 788776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A4	NM_032279.4	c.182A>G	p.His61Arg	missense_variant	2/30	ENST00000342695.9	NP_115655.2
ATP13A4	XM_047449063.1	c.311A>G	p.His104Arg	missense_variant	4/32		XP_047305019.1
ATP13A4	XM_017007319.2	c.311A>G	p.His104Arg	missense_variant	4/27		XP_016862808.2
ATP13A4	XR_007095757.1	n.575A>G		non_coding_transcript_exon_variant	4/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A4	ENST00000342695.9	c.182A>G	p.His61Arg	missense_variant	2/30	1	NM_032279.4	ENSP00000339182	P1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00373

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00241 AC: 606 AN: 251418 Hom.: 1 AF XY: 0.00222 AC XY: 301 AN XY: 135880

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00439

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00368 AC: 5379 AN: 1461884 Hom.: 15 Cov.: 31 AF XY: 0.00355 AC XY: 2579 AN XY: 727242

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00440

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00443

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74452

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00373

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00338 Hom.: 1

Bravo AF: 0.00247

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00234 AC: 284

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00397

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 27, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ATP13A4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2023

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	0.080
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.0024	T;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.34	.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.029
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.31
MVP		0.14
MPC		0.14
ClinPred		0.0047	T
GERP RS		3.4
Varity_R		0.049
gMVP		0.67

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: rs142942671; hg19: chr3-193232539;