rs995020305

Variant names:

• chr3-193279433-A-G
• rs995020305
• NM_198505.4:c.3248T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-193279433-A-G
• chr3-193279433-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198505.4(ATP13A5):​c.3248T>C​(p.Leu1083Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ATP13A5 NM_198505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.699
• Publications: 0 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]

PLAAT1 (HGNC:14922): (phospholipase A and acyltransferase 1) Enables acyltransferase activity, transferring groups other than amino-acyl groups and phospholipase activity. Involved in N-acylphosphatidylethanolamine metabolic process and phosphatidylcholine metabolic process. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38379547).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A5	NM_198505.4	MANE Select	c.3248T>C	p.Leu1083Pro	missense	Exon 28 of 30	NP_940907.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A5	ENST00000342358.9	TSL:1 MANE Select	c.3248T>C	p.Leu1083Pro	missense	Exon 28 of 30	ENSP00000341942.4	Q4VNC0
	ATP13A5	ENST00000495496.1	TSL:5	n.1070T>C		non_coding_transcript_exon	Exon 10 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461348 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727022

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111596

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.70
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.61
MutPred		0.60		Gain of catalytic residue at L1083 (P = 0.0192)
MVP		0.14
MPC		0.13
ClinPred		0.031	T
GERP RS		-0.65
Varity_R		0.32
gMVP		0.79
Mutation Taster		=95/5	polymorphism

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: rs995020305; hg19: chr3-192997222;