rs55831733

chr1-20645615-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_032409.3(PINK1):c.1015G>A(p.Ala339Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,680 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A339A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: PINK1 NM_032409.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6
• Conservation: PhyloP100: 2.93

Genes affected

PINK1 (HGNC:14581): (PTEN induced kinase 1) This gene encodes a serine/threonine protein kinase that localizes to mitochondria. It is thought to protect cells from stress-induced mitochondrial dysfunction. Mutations in this gene cause one form of autosomal recessive early-onset Parkinson disease. [provided by RefSeq, Jul 2008]

PINK1-AS (HGNC:38872): (PINK1 antisense RNA)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PINK1	NM_032409.3	c.1015G>A	p.Ala339Thr	missense_variant	5/8	ENST00000321556.5
PINK1-AS	NR_046507.1	n.3951C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINK1	ENST00000321556.5	c.1015G>A	p.Ala339Thr	missense_variant	5/8	1	NM_032409.3	P1
PINK1-AS	ENST00000451424.1	n.3951C>T		non_coding_transcript_exon_variant	2/3	2
PINK1	ENST00000400490.2	n.108G>A		non_coding_transcript_exon_variant	1/4	2
PINK1	ENST00000492302.1	n.2103G>A		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.000732 AC: 111 AN: 151738 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000585 AC: 147 AN: 251376 Hom.: 0 AF XY: 0.000545 AC XY: 74 AN XY: 135888

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000915

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00140 AC: 2046 AN: 1461826 Hom.: 3 Cov.: 38 AF XY: 0.00131 AC XY: 954 AN XY: 727216

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.000731 AC: 111 AN: 151854 Hom.: 0 Cov.: 32 AF XY: 0.000660 AC XY: 49 AN XY: 74226

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.00112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.000952

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000710

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.00115

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	Reported as a heterozygous variant in patients with Parkinson disease in published literature (Rogaeva et al., 2004; Abou-Sleiman et al., 2006; Gadhi et al., 2006; Peterson et al., 2015); Published functional studies suggest that A339T may have a damaging effect on protein function (Tan et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16969854, 18330912, 19351622, 22451330, 21412950, 16547921, 16702191, 24374372, 25466404, 15596610, 20981092, 19847793, 22644621, 24441527, 18403612, 28849312) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2017	The p.Ala339Thr variant (rs55831733) has been reported as a heterozygote in several individuals included in cohorts of Parkinson’s disease (PD) patients while being absent or rare in controls (Abou-Sleiman 2006, Brooks 2009, Gandhi 2006, Marongiu 2008, Petersen 2015, Rogaeva 2004). However, this putative enrichment in patient populations has never been supported statistically and co-segregation of the p.Ala339Thr variant with PD has not been reported. Furthermore, in despite of research efforts, the impact of heterozygous PINK1 variants on the development of PD is not completely understood, and PINK1 variants are classically associated with autosomal recessive inheritance (see link to GeneReviews). None the less, expression of p.Ala339Thr variant protein in cell culture has been shown to sensitize cells to oxidative stress resulting in increased apoptosis compared with expression of wild-type PINK1 (Tan 2009 and Zhou 2014). This variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.05% (identified in 157 out of 277,112 chromosomes). Taken together, the clinical significance of the p.Ala339Thr variant cannot be determined with certainty. -

Autosomal recessive early-onset Parkinson disease 6 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 22, 2022	This sequence change is predicted to replace alanine with threonine at codon 339 of the PINK1 protein (p.(Ala339Thr)). The alanine residue is moderately conserved (100 vertebrates, UCSC), and is located in the protein kinase domain. There is a small physicochemical difference between alanine and threonine. The variant is present in a large population cohort at a frequency of 0.06% (rs55831733, 163/282,728 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified compound heterozygous with a PINK1 variant of uncertain significance in an individual with a dystonia-Parkinsonism phenotype (PMID: 28849312). It has been identified heterozygous in multiple individuals with Parkinson disease, but is not significantly increased compared with the prevalence in controls (PMID: 15596610, 16702191, 16969854, 18330912, 25466404). In vitro functional assays demonstrate the variant causes increased sensitivity to oxidative stress in dopaminergic neurons (PMID: 19847793, 24374372). Multiple lines of computational evidence predict a benign effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS3_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 339 of the PINK1 protein (p.Ala339Thr). This variant is present in population databases (rs55831733, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 15596610, 16702191, 18330912, 18403612, 19351622, 25466404, 28849312). ClinVar contains an entry for this variant (Variation ID: 500148). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PINK1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PINK1 function (PMID: 19847793, 24374372). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.39
Sift	Benign	0.045	D
Sift4G	Benign	0.24	T
Polyphen		0.98	D
Vest4		0.83
MVP		0.91
MPC		0.59
ClinPred		0.033	T
GERP RS		5.1
Varity_R		0.044
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs55831733; hg19: chr1-20972108; COSMIC: COSV100387364;