rs149953814

chr6-161350187-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_004562.3(PRKN):c.1310C>T(p.Pro437Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00274 in 1,613,282 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P437A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (8 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 5.57

Genes affected

PRKN (HGNC:8607): (parkin RBR E3 ubiquitin protein ligase) The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004562.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.030217081).
• BP6: Variant 6-161350187-G-A is Benign according to our data. Variant chr6-161350187-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283504.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.1310C>T	p.Pro437Leu	missense_variant	12/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6	c.1310C>T	p.Pro437Leu	missense_variant	12/12	1	NM_004562.3	P1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152124 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00343

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00159 AC: 396 AN: 249654 Hom.: 0 AF XY: 0.00152 AC XY: 206 AN XY: 135300

Gnomad AFR exome AF: 0.000499

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.000898

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00280 AC: 4093 AN: 1461040 Hom.: 8 Cov.: 31 AF XY: 0.00266 AC XY: 1930 AN XY: 726804

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000245

Gnomad4 NFE exome AF: 0.00336

Gnomad4 OTH exome AF: 0.00345

GnomAD4 genome AF: 0.00212 AC: 322 AN: 152242 Hom.: 1 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74450

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00343

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00244 Hom.: 1

Bravo AF: 0.00226

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00138 AC: 167

EpiCase AF: 0.00229

EpiControl AF: 0.00232

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2022	Reported previously in an individual with early onset Parkinson disease who also harbored a second PRKN variant; however, parental studies were not performed (Djarmati et al., 2004); Reported previously as pathogenic in an individual with Parkinson disease who also harbored a complex locus rearrangement presumed to be on the other allele; however, parental testing was not performed and detailed clinical information was not available (Robak et al., 2020); Reported previously in the heterozygous state in individuals with Parkinson disease; however, it was also observed in unaffected controls (Langston et al., 2007; Moura et al., 2013; Pihlstrom et al., 2014; Gustavsson et al., 2017; Jankovic et al., 2018); Published functional studies demonstrate a damaging effect showing that P437L significantly reduced binding ability and ubiquitination activity of parkin (Sriram et al., 2005; Williams et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24660942, 32802956, 16049031, 33751372, 33045815, 33845304, 29893854, 30363439, 30099245, 17187375, 19636047, 12629236, 26683220, 29887346, 28189762, 18546294, 24167364, 17262853, 30994895, 20643691, 15108293, 34426522, 34434164, 34584092) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 20, 2024

Variant summary: PRF1 c.1310C>T (p.Ala437Val) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 250636 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (0.00073 vs 0.0027), allowing no conclusion about variant significance. c.1310C>T has been reported in the literature in individuals affected with Familial Hemophagocytic Lymphohistiocytosis. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive juvenile Parkinson disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;.;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D;D;.;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.030	T;T;T;T;T;T
MetaSVM	Uncertain	-0.024	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N;N;N;.;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.055	T;T;D;.;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.55
MVP		0.95
MPC		0.36
ClinPred		0.028	T
GERP RS		5.3
Varity_R		0.53
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs149953814; hg19: chr6-161771219; COSMIC: COSV58235952;