rs74437357

Positions:

• chr3-193334980-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_198505.4(ATP13A5):​c.1063C>T​(p.Gln355*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,613,820 control chromosomes in the GnomAD database, including 863 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.023 (42 hom., cov: 32)
  • Exomes 𝑓: 0.030 (821 hom.)
• Consequence: ATP13A5 NM_198505.4 stop_gained
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.68

Genes affected

ATP13A5 (HGNC:31789): (ATPase 13A5) This gene encodes a member of the P5 subfamily of P-type transport ATPases. P-type ATPases form a large superfamily of cation and lipid pumps that transport inorganic cations and other substrates across cell membranes. P5 ATPases are localized to membranes of the endoplasmic reticulum (ER) and serve many important functions including transport of cargo proteins to the Golgi, glycosylation and cell wall biosynthesis, control of protein insertion orientation, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) degradation, and sensitivity to unfolded protein response (UPR) activators. The encoded protein is organized into three cytoplasmic domains (A, P, and N) and two membrane-embedded domains (T and S). The N-domain binds ATP and serves as a built-in protein kinase, which phosphorylates the P-domain. The A-domain is an intrinsic protein phosphatase, which dephosphorylates the P-domain once during each catalytic cycle. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 3-193334980-G-A is Benign according to our data. Variant chr3-193334980-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 402400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193334980-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0231 (3512/152282) while in subpopulation NFE AF= 0.0337 (2291/68016). AF 95% confidence interval is 0.0325. There are 42 homozygotes in gnomad4. There are 1750 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A5	NM_198505.4	c.1063C>T	p.Gln355*	stop_gained	10/30	ENST00000342358.9	NP_940907.2
ATP13A5	XM_011512770.3	c.1063C>T	p.Gln355*	stop_gained	10/27		XP_011511072.1
ATP13A5	XM_047448075.1	c.19-3669C>T		intron_variant			XP_047304031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A5	ENST00000342358.9	c.1063C>T	p.Gln355*	stop_gained	10/30	1	NM_198505.4	ENSP00000341942.4

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3512 AN: 152164 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00557

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0220 AC: 5520 AN: 251162 Hom.: 97 AF XY: 0.0219 AC XY: 2968 AN XY: 135732

Gnomad AFR exome AF: 0.00499

Gnomad AMR exome AF: 0.00926

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00644

Gnomad FIN exome AF: 0.0491

Gnomad NFE exome AF: 0.0322

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0299 AC: 43716 AN: 1461538 Hom.: 821 Cov.: 31 AF XY: 0.0291 AC XY: 21166 AN XY: 727052

Gnomad4 AFR exome AF: 0.00514

Gnomad4 AMR exome AF: 0.00859

Gnomad4 ASJ exome AF: 0.00834

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00665

Gnomad4 FIN exome AF: 0.0480

Gnomad4 NFE exome AF: 0.0343

Gnomad4 OTH exome AF: 0.0267

GnomAD4 genome AF: 0.0231 AC: 3512 AN: 152282 Hom.: 42 Cov.: 32 AF XY: 0.0235 AC XY: 1750 AN XY: 74474

Gnomad4 AFR AF: 0.00556

Gnomad4 AMR AF: 0.0205

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.0498

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0292 Hom.: 106

Bravo AF: 0.0201

TwinsUK AF: 0.0418 AC: 155

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0298 AC: 256

ExAC AF: 0.0217 AC: 2633

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0307

EpiControl AF: 0.0282

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.35
GERP RS		5.9

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: rs74437357; hg19: chr3-193052769;