chr1-7962764-C-T

Position:

• chr1-7962764-C-T

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.-22C>T variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00786 in 1,235,092 control chromosomes in the GnomAD database, including 546 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (289 hom., cov: 29)
  • Exomes 𝑓: 0.0043 (257 hom.)
• Consequence: PARK7 NM_007262.5 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.00001403
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.706

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=-0.85).
• BP6: Variant 1-7962764-C-T is Benign according to our data. Variant chr1-7962764-C-T is described in ClinVar as [Benign]. Clinvar id is 298117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARK7	NM_007262.5	c.-22C>T		splice_region_variant, 5_prime_UTR_variant	2/7	ENST00000338639.10	NP_009193.2
PARK7	NM_001123377.2	c.-22C>T		splice_region_variant, 5_prime_UTR_variant	2/7		NP_001116849.1
PARK7	XM_005263424.4	c.-22C>T		splice_region_variant, 5_prime_UTR_variant	2/7		XP_005263481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARK7	ENST00000338639.10	c.-22C>T		splice_region_variant, 5_prime_UTR_variant	2/7	1	NM_007262.5	ENSP00000340278	P1

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 4959 AN: 129676 Hom.: 288 Cov.: 29

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000489

Gnomad FIN AF: 0.000483

Gnomad MID AF: 0.0122

Gnomad NFE AF: 0.000404

Gnomad OTH AF: 0.0293

GnomAD3 exomes AF: 0.00965 AC: 2136 AN: 221380 Hom.: 107 AF XY: 0.00712 AC XY: 856 AN XY: 120244

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.00583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000189

Gnomad FIN exome AF: 0.000133

Gnomad NFE exome AF: 0.000331

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00429 AC: 4737 AN: 1105350 Hom.: 257 Cov.: 20 AF XY: 0.00369 AC XY: 2070 AN XY: 561640

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.00706

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000295

Gnomad4 FIN exome AF: 0.000213

Gnomad4 NFE exome AF: 0.000159

Gnomad4 OTH exome AF: 0.00966

GnomAD4 genome AF: 0.0383 AC: 4966 AN: 129742 Hom.: 289 Cov.: 29 AF XY: 0.0385 AC XY: 2374 AN XY: 61644

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0162

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000491

Gnomad4 FIN AF: 0.000483

Gnomad4 NFE AF: 0.000404

Gnomad4 OTH AF: 0.0291

Alfa AF: 0.00755 Hom.: 28

Bravo AF: 0.0399

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 30, 2020

- -

Autosomal recessive early-onset Parkinson disease 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.85
CADD	Benign	9.4
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs11548933; hg19: chr1-8022824;