rs139226733

Variant names:

• chr1-20644665-A-T
• rs139226733
• NM_032409.3:c.952A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-20644665-A-T
• chr1-20644665-A-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_032409.3(PINK1):​c.952A>T​(p.Met318Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000737 in 1,614,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (1 hom.)
• Consequence: PINK1 NM_032409.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:13
• Conservation: PhyloP100: 8.04
• Publications: 14 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07187414).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00086 (131/152340) while in subpopulation NFE AF = 0.00128 (87/68024). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.952A>T	p.Met318Leu	missense	Exon 4 of 8	NP_115785.1	Q9BXM7-1
	PINK1-AS	NR_046507.1		n.3981+920T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.952A>T	p.Met318Leu	missense	Exon 4 of 8	ENSP00000364204.3	Q9BXM7-1
	PINK1	ENST00000878749.1		c.952A>T	p.Met318Leu	missense	Exon 4 of 8	ENSP00000548808.1
	PINK1	ENST00000878743.1		c.952A>T	p.Met318Leu	missense	Exon 4 of 8	ENSP00000548802.1

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000900 AC: 226 AN: 251094 AF XY: 0.000847

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000724 AC: 1058 AN: 1461832 Hom.: 1 Cov.: 31 AF XY: 0.000688 AC XY: 500 AN XY: 727224

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53368

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000769 AC: 855 AN: 1112004

Other (OTH) AF: 0.000679 AC: 41 AN: 60396

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000872 AC XY: 65 AN XY: 74502

African (AFR) AF: 0.000168 AC: 7 AN: 41584

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00102 AC: 124

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	Autosomal recessive early-onset Parkinson disease 6 (5)
-	5	-	not provided (5)
-	2	-	not specified (2)
-	1	-	PINK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Polyphen		0.089	B
Vest4		0.77
MutPred		0.88		Gain of methylation at K319 (P = 0.0356)
MVP		0.88
MPC		0.20
ClinPred		0.077	T
GERP RS		6.1
Varity_R		0.67
gMVP		0.76
Mutation Taster		=30/70	disease causing

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: rs139226733; hg19: chr1-20971158;