rs71653619

Positions:

chr1-7970934-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000338639.10(PARK7):c.293G>A(p.Arg98Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00932 in 1,614,132 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 99 hom. )

Consequence

PARK7
ENST00000338639.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.37

Variant links:

Genes affected

PARK7 (HGNC:16369): (Parkinsonism associated deglycase) The product of this gene belongs to the peptidase C56 family of proteins. It acts as a positive regulator of androgen receptor-dependent transcription. It may also function as a redox-sensitive chaperone, as a sensor for oxidative stress, and it apparently protects neurons against oxidative stress and cell death. Defects in this gene are the cause of autosomal recessive early-onset Parkinson disease 7. Two transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

PARK7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007415414).

BP6

Variant 1-7970934-G-A is Benign according to our data. Variant chr1-7970934-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 465831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-7970934-G-A is described in Lovd as [Likely_benign]. Variant chr1-7970934-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00715 (1088/152266) while in subpopulation NFE AF= 0.0114 (774/68014). AF 95% confidence interval is 0.0107. There are 5 homozygotes in gnomad4. There are 483 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PARK7	NM_007262.5 linkuse as main transcript	c.293G>A	p.Arg98Gln	missense_variant	5/7	ENST00000338639.10	NP_009193.2
PARK7	NM_001123377.2 linkuse as main transcript	c.293G>A	p.Arg98Gln	missense_variant	5/7		NP_001116849.1
PARK7	XM_005263424.4 linkuse as main transcript	c.293G>A	p.Arg98Gln	missense_variant	5/7		XP_005263481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARK7	ENST00000338639.10 linkuse as main transcript	c.293G>A	p.Arg98Gln	missense_variant	5/7	1	NM_007262.5	ENSP00000340278	P1

Frequencies

GnomAD3 genomes

AF:

0.00715

AC:

1088

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00863

GnomAD3 exomes

AF:

0.00789

AC:

1984

AN:

251484

Hom.:

AF XY:

0.00853

AC XY:

1159

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00598

Gnomad ASJ exome

AF:

0.00982

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0114

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00879

GnomAD4 exome

AF:

0.00955

AC:

13957

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00970

AC XY:

7051

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.00606

Gnomad4 ASJ exome

AF:

0.0111

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0122

Gnomad4 FIN exome

AF:

0.00127

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.00940

GnomAD4 genome

AF:

0.00715

AC:

1088

AN:

152266

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

483

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.00894

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0108

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.0114

Gnomad4 OTH

AF:

0.00854

Alfa

AF:

0.00970

Hom.:

Bravo

AF:

0.00706

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.00815

AC:

989

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PARK7: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	This variant is associated with the following publications: (PMID: 25466404, 16997464, 27535533, 17504761, 15254937, 15790532, 26274610, 27884173, 27592010, 12891685, 22428580, 22995991, 22960331, 15219840, 22173095, 14705128) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive early-onset Parkinson disease 7

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 26, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

- -

Renal cysts and diabetes syndrome

Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Arg98Gln variant in PARK7 has been identified in 3 individuals with Parkinson disease (PMID: 12891685, 14705128), but has also been identified in >1% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg98Gln variant may impact protein function (PMID: 22428580, 15219840, 15790532). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive Parkinson disease. -

PARK7-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.21

T;T;T;T;T;T;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

.;.;.;T;.;T;T

MetaRNN

Benign

0.0074

T;T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.56

N;N;N;.;N;N;.

MutationTaster

Benign

0.98

N;N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.23

.;N;N;.;N;N;.

REVEL

Benign

0.20

Sift

Benign

0.51

.;T;T;.;T;T;.

Sift4G

Benign

0.62

T;T;T;T;T;T;T

Polyphen

0.0050

B;B;B;.;B;B;.

Vest4

0.40, 0.37, 0.38

MVP

0.60

MPC

0.15

ClinPred

0.0021

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over