rs71653621

Positions:

• chr1-7984985-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_007262.5(PARK7):​c.501A>G​(p.Ala167=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,160 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: PARK7 NM_007262.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.69

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-7984985-A-G is Benign according to our data. Variant chr1-7984985-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 707607.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr1-7984985-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.68 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARK7	NM_007262.5	c.501A>G	p.Ala167=	synonymous_variant	7/7	ENST00000338639.10	NP_009193.2
PARK7	NM_001123377.2	c.501A>G	p.Ala167=	synonymous_variant	7/7		NP_001116849.1
PARK7	XM_005263424.4	c.501A>G	p.Ala167=	synonymous_variant	7/7		XP_005263481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARK7	ENST00000338639.10	c.501A>G	p.Ala167=	synonymous_variant	7/7	1	NM_007262.5	ENSP00000340278	P1

Frequencies

GnomAD3 genomes AF: 0.000914 AC: 139 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00126 AC: 317 AN: 251478 Hom.: 2 AF XY: 0.00121 AC XY: 165 AN XY: 135910

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00698

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00105 AC: 1530 AN: 1461888 Hom.: 4 Cov.: 30 AF XY: 0.000972 AC XY: 707 AN XY: 727248

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00702

Gnomad4 NFE exome AF: 0.000968

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74438

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00688

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000732 Hom.: 0

Bravo AF: 0.000408

EpiCase AF: 0.000872

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive early-onset Parkinson disease 7 Uncertain:1 Benign:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

PARK7: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.40
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs71653621; hg19: chr1-8045045;