chr1-20645615-G-A

Variant names:

• chr1-20645615-G-A
• rs55831733
• NM_032409.3:c.1015G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

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 Uncertain significance (★★). 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: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 2.93
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000731 (111/151854) while in subpopulation AMR AF = 0.00112 (17/15240). AF 95% confidence interval is 0.000876. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032409.3. 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
	PINK1	NM_032409.3	MANE Select	c.1015G>A	p.Ala339Thr	missense	Exon 5 of 8	NP_115785.1	Q9BXM7-1
	PINK1-AS	NR_046507.1		n.3951C>T		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.1015G>A	p.Ala339Thr	missense	Exon 5 of 8	ENSP00000364204.3	Q9BXM7-1
	PINK1	ENST00000878749.1		c.1015G>A	p.Ala339Thr	missense	Exon 5 of 8	ENSP00000548808.1
	PINK1	ENST00000878743.1		c.1015G>A	p.Ala339Thr	missense	Exon 5 of 8	ENSP00000548802.1

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

GnomAD2 exomes AF: 0.000585 AC: 147 AN: 251376 AF XY: 0.000545

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 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

African (AFR) AF: 0.000358 AC: 12 AN: 33478

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53382

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00172 AC: 1916 AN: 1111988

Other (OTH) AF: 0.00119 AC: 72 AN: 60396

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

African (AFR) AF: 0.000386 AC: 16 AN: 41438

American (AMR) AF: 0.00112 AC: 17 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 67958

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

Alfa AF: 0.00170 Hom.: 1

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	6	-	not provided (6)
-	3	-	Autosomal recessive early-onset Parkinson disease 6 (3)
-	1	-	not specified (1)
-	1	-	PINK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.9
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
Mutation Taster		=82/18	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs55831733; hg19: chr1-20972108; COSMIC: COSV100387364;