rs74437357

Variant names:

• chr3-193334980-G-A
• rs74437357
• NM_198505.4:c.1063C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 402400.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 = 0.0231 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198505.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A5	NM_198505.4	MANE Select	c.1063C>T	p.Gln355*	stop_gained	Exon 10 of 30	NP_940907.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A5	ENST00000342358.9	TSL:1 MANE Select	c.1063C>T	p.Gln355*	stop_gained	Exon 10 of 30	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

GnomAD2 exomes AF: 0.0220 AC: 5520 AN: 251162 AF XY: 0.0219

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 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

African (AFR) AF: 0.00514 AC: 172 AN: 33462

American (AMR) AF: 0.00859 AC: 384 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00834 AC: 218 AN: 26124

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.00665 AC: 573 AN: 86210

European-Finnish (FIN) AF: 0.0480 AC: 2564 AN: 53418

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5764

European-Non Finnish (NFE) AF: 0.0343 AC: 38164 AN: 1111772

Other (OTH) AF: 0.0267 AC: 1614 AN: 60388

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

African (AFR) AF: 0.00556 AC: 231 AN: 41570

American (AMR) AF: 0.0205 AC: 314 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4824

European-Finnish (FIN) AF: 0.0498 AC: 529 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2291 AN: 68016

Other (OTH) AF: 0.0156 AC: 33 AN: 2112

Alfa AF: 0.0282 Hom.: 231

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.7
Vest4		0.35
GERP RS		5.9
Mutation Taster		=43/157	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74437357; hg19: chr3-193052769;