rs148871409

Variant names:

• chr1-20633892-A-T
• rs148871409
• NM_032409.3:c.344A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-20633892-A-T
• chr1-20633892-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032409.3(PINK1):​c.344A>T​(p.Gln115Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,582,768 control chromosomes in the GnomAD database, including 1,905 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q115H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.035 (139 hom., cov: 31)
  • Exomes 𝑓: 0.047 (1766 hom.)
• Consequence: PINK1 NM_032409.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.17
• Publications: 24 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]

MIR6084 (HGNC:50235): (microRNA 6084) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015456975).
• BP6: Variant 1-20633892-A-T is Benign according to our data. Variant chr1-20633892-A-T is described in ClinVar as Benign. ClinVar VariationId is 294999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

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.344A>T	p.Gln115Leu	missense	Exon 1 of 8	NP_115785.1	Q9BXM7-1
	MIR6084	NR_106732.1		n.*104A>T		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.344A>T	p.Gln115Leu	missense	Exon 1 of 8	ENSP00000364204.3	Q9BXM7-1
	PINK1	ENST00000878749.1		c.344A>T	p.Gln115Leu	missense	Exon 1 of 8	ENSP00000548808.1
	PINK1	ENST00000878743.1		c.344A>T	p.Gln115Leu	missense	Exon 1 of 8	ENSP00000548802.1

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5352 AN: 151192 Hom.: 139 Cov.: 31

Gnomad AFR AF: 0.00966

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00583

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.0256

Gnomad NFE AF: 0.0548

Gnomad OTH AF: 0.0304

GnomAD2 exomes AF: 0.0333 AC: 6238 AN: 187552 AF XY: 0.0333

Gnomad AFR exome AF: 0.00788

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0411

Gnomad NFE exome AF: 0.0541

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0470 AC: 67226 AN: 1431472 Hom.: 1766 Cov.: 36 AF XY: 0.0457 AC XY: 32427 AN XY: 709674

African (AFR) AF: 0.00730 AC: 240 AN: 32898

American (AMR) AF: 0.0218 AC: 887 AN: 40716

Ashkenazi Jewish (ASJ) AF: 0.0348 AC: 891 AN: 25584

East Asian (EAS) AF: 0.0000523 AC: 2 AN: 38218

South Asian (SAS) AF: 0.00704 AC: 579 AN: 82258

European-Finnish (FIN) AF: 0.0446 AC: 2163 AN: 48516

Middle Eastern (MID) AF: 0.0109 AC: 58 AN: 5322

European-Non Finnish (NFE) AF: 0.0548 AC: 60192 AN: 1098794

Other (OTH) AF: 0.0374 AC: 2214 AN: 59166

GnomAD4 genome AF: 0.0354 AC: 5349 AN: 151296 Hom.: 139 Cov.: 31 AF XY: 0.0339 AC XY: 2507 AN XY: 73926

African (AFR) AF: 0.00964 AC: 396 AN: 41094

American (AMR) AF: 0.0300 AC: 456 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3464

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5072

South Asian (SAS) AF: 0.00584 AC: 28 AN: 4794

European-Finnish (FIN) AF: 0.0447 AC: 467 AN: 10450

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0548 AC: 3722 AN: 67904

Other (OTH) AF: 0.0301 AC: 63 AN: 2094

Alfa AF: 0.0475 Hom.: 66

Bravo AF: 0.0326

TwinsUK AF: 0.0380 AC: 141

ALSPAC AF: 0.0449 AC: 173

ESP6500AA AF: 0.00658 AC: 25

ESP6500EA AF: 0.0450 AC: 360

ExAC AF: 0.0284 AC: 3311

Asia WGS AF: 0.00433 AC: 16 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.11
Sift	Benign	0.32	T
Sift4G	Benign	0.20	T
Polyphen		0.12	B
Vest4		0.098
MPC		0.17
ClinPred		0.0044	T
GERP RS		3.9
PromoterAI		-0.0025	Neutral
Varity_R		0.11
gMVP		0.49
Mutation Taster		=84/16	polymorphism (auto)

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: rs148871409; hg19: chr1-20960385;