1-7961718-T-C

Position:

• chr1-7961718-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007262.5(PARK7):​c.-99T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.658 in 153,016 control chromosomes in the GnomAD database, including 34,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34182 hom., cov: 34)
  • Exomes 𝑓: 0.53 (129 hom.)
• Consequence: PARK7 NM_007262.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.817

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-7961718-T-C is Benign according to our data. Variant chr1-7961718-T-C is described in ClinVar as [Benign]. Clinvar id is 298113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-7961718-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARK7	NM_007262.5	c.-99T>C		5_prime_UTR_variant	1/7	ENST00000338639.10	NP_009193.2
PARK7	NM_001123377.2	c.-41T>C		5_prime_UTR_variant	1/7		NP_001116849.1
PARK7	XM_005263424.4	c.-387T>C		5_prime_UTR_variant	1/7		XP_005263481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARK7	ENST00000338639.10	c.-99T>C		5_prime_UTR_variant	1/7	1	NM_007262.5	ENSP00000340278	P1

Frequencies

GnomAD3 genomes AF: 0.658 AC: 100038 AN: 152038 Hom.: 34129 Cov.: 34

Gnomad AFR AF: 0.844

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.616

GnomAD4 exome AF: 0.535 AC: 462 AN: 864 Hom.: 129 Cov.: 0 AF XY: 0.540 AC XY: 350 AN XY: 648

Gnomad4 AFR exome AF: 0.900

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.529

Gnomad4 NFE exome AF: 0.552

Gnomad4 OTH exome AF: 0.682

GnomAD4 genome AF: 0.658 AC: 100149 AN: 152152 Hom.: 34182 Cov.: 34 AF XY: 0.656 AC XY: 48769 AN XY: 74382

Gnomad4 AFR AF: 0.844

Gnomad4 AMR AF: 0.655

Gnomad4 ASJ AF: 0.547

Gnomad4 EAS AF: 0.633

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.632

Gnomad4 NFE AF: 0.581

Gnomad4 OTH AF: 0.610

Alfa AF: 0.591 Hom.: 7656

Bravo AF: 0.677

Asia WGS AF: 0.526 AC: 1829 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Autosomal recessive early-onset Parkinson disease 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.53
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs226249; hg19: chr1-8021778;