3-193311926-T-C

Variant names:

• chr3-193311926-T-C
• rs145000399
• NM_198505.4:c.2335A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198505.4(ATP13A5):​c.2335A>G​(p.Thr779Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000838 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (0 hom.)
• Consequence: ATP13A5 NM_198505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0190

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]

ATP13A5-AS1 (HGNC:41281): (ATP13A5 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018982887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A5	NM_198505.4	c.2335A>G	p.Thr779Ala	missense_variant	Exon 20 of 30	ENST00000342358.9	NP_940907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A5	ENST00000342358.9	c.2335A>G	p.Thr779Ala	missense_variant	Exon 20 of 30	1	NM_198505.4	ENSP00000341942.4
ATP13A5	ENST00000495496.1	n.157A>G		non_coding_transcript_exon_variant	Exon 2 of 12	5
ATP13A5-AS1	ENST00000414634.1	n.158-2118T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000721 AC: 181 AN: 250978 Hom.: 0 AF XY: 0.000723 AC XY: 98 AN XY: 135620

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000854 AC: 1248 AN: 1461510 Hom.: 0 Cov.: 30 AF XY: 0.000900 AC XY: 654 AN XY: 727060

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74486

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000894 Hom.: 0

Bravo AF: 0.000623

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000626 AC: 76

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000891

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2335A>G (p.T779A) alteration is located in exon 20 (coding exon 20) of the ATP13A5 gene. This alteration results from a A to G substitution at nucleotide position 2335, causing the threonine (T) at amino acid position 779 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	3.6
DANN	Benign	0.73
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.32	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.19
Sift	Benign	0.71	T
Sift4G	Benign	0.77	T
Polyphen		0.0030	B
Vest4		0.20
MVP		0.21
MPC		0.078
ClinPred		0.0054	T
GERP RS		3.0
Varity_R		0.045
gMVP		0.16

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: rs145000399; hg19: chr3-193029715;