3-194419935-T-A

Variant names:

• chr3-194419935-T-A
• rs200180433
• NM_001367549.1:c.3346A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001367549.1(ATP13A3):​c.3346A>T​(p.Ile1116Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000885 in 1,536,090 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1116T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000091 (1 hom.)
• Consequence: ATP13A3 NM_001367549.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.225
• Publications: 1 publications found

Genes affected

ATP13A3 (HGNC:24113): (ATPase 13A3) ATP13A3 is a member of the P-type ATPase family of proteins that transport a variety of cations across membranes. Other P-type ATPases include ATP7B (MIM 606882) and ATP7A (MIM 300011).[supplied by OMIM, Aug 2008]

ATP13A3 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06294325).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367549.1. 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
	ATP13A3	NM_001367549.1	MANE Select	c.3346A>T	p.Ile1116Phe	missense	Exon 31 of 34	NP_001354478.1	A0A2R8Y635
	ATP13A3	NM_001374836.1		c.3265A>T	p.Ile1089Phe	missense	Exon 30 of 33	NP_001361765.1
	ATP13A3	NM_001437993.1		c.3346A>T	p.Ile1116Phe	missense	Exon 31 of 33	NP_001424922.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A3	ENST00000645319.2	MANE Select	c.3346A>T	p.Ile1116Phe	missense	Exon 31 of 34	ENSP00000494937.2	A0A2R8Y635
	ATP13A3	ENST00000429136.7	TSL:1	n.1192A>T		non_coding_transcript_exon	Exon 10 of 13
	ATP13A3	ENST00000461660.2	TSL:1	n.450A>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0000659 AC: 10 AN: 151722 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0000538 AC: 10 AN: 185866 AF XY: 0.0000578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000556

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000992

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000910 AC: 126 AN: 1384250 Hom.: 1 Cov.: 30 AF XY: 0.0000857 AC XY: 59 AN XY: 688268

African (AFR) AF: 0.000105 AC: 3 AN: 28620

American (AMR) AF: 0.0000371 AC: 1 AN: 26936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23162

East Asian (EAS) AF: 0.00 AC: 0 AN: 36964

South Asian (SAS) AF: 0.00 AC: 0 AN: 72552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51216

Middle Eastern (MID) AF: 0.000604 AC: 3 AN: 4970

European-Non Finnish (NFE) AF: 0.000108 AC: 117 AN: 1083254

Other (OTH) AF: 0.0000354 AC: 2 AN: 56576

GnomAD4 genome AF: 0.0000659 AC: 10 AN: 151840 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74230

African (AFR) AF: 0.0000724 AC: 3 AN: 41414

American (AMR) AF: 0.000263 AC: 4 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10480

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67944

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000136 Hom.: 1

Bravo AF: 0.0000604

ExAC AF: 0.0000748 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	3.5
DANN	Benign	0.81
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.23
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.13
Sift	Benign	0.65	T
Sift4G	Benign	0.081	T
Polyphen		0.0	B
Vest4		0.095
MVP		0.40
MPC		0.57
ClinPred		0.042	T
GERP RS		2.8
Varity_R		0.023
gMVP		0.60
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200180433; hg19: chr3-194140664;