1-7962740-CTTTTTTTT-CTTTTTTTTTT

Variant names:

• chr1-7962740-C-CTT
• rs370370394
• NM_007262.5:c.-23-5_-23-4dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007262.5(PARK7):​c.-23-5_-23-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,143,458 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0059 (0 hom.)
• Consequence: PARK7 NM_007262.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive early-onset Parkinson disease 7

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.00625) population. However there is too low homozygotes in high coverage region: (expected more than 8, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007262.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARK7	NM_007262.5	MANE Select	c.-23-5_-23-4dupTT		splice_region intron	N/A	NP_009193.2
	PARK7	NM_001123377.2		c.-23-5_-23-4dupTT		splice_region intron	N/A	NP_001116849.1	Q99497

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARK7	ENST00000338639.10	TSL:1 MANE Select	c.-23-5_-23-4dupTT		splice_region intron	N/A	ENSP00000340278.5	Q99497
	PARK7	ENST00000493678.5	TSL:1	c.-23-5_-23-4dupTT		splice_region intron	N/A	ENSP00000418770.1	Q99497
	PARK7	ENST00000872631.1		c.-28_-27dupTT		5_prime_UTR	Exon 1 of 6	ENSP00000542690.1

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 13 AN: 115180 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000891

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00762 AC: 686 AN: 89970 AF XY: 0.00761

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.00763

Gnomad ASJ exome AF: 0.00662

Gnomad EAS exome AF: 0.00687

Gnomad FIN exome AF: 0.00316

Gnomad NFE exome AF: 0.00893

Gnomad OTH exome AF: 0.00924

GnomAD4 exome AF: 0.00594 AC: 6111 AN: 1028290 Hom.: 0 Cov.: 0 AF XY: 0.00570 AC XY: 2968 AN XY: 520480

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00385 AC: 86 AN: 22338

American (AMR) AF: 0.00427 AC: 118 AN: 27638

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 106 AN: 20432

East Asian (EAS) AF: 0.00295 AC: 96 AN: 32550

South Asian (SAS) AF: 0.00504 AC: 329 AN: 65238

European-Finnish (FIN) AF: 0.00389 AC: 137 AN: 35180

Middle Eastern (MID) AF: 0.00268 AC: 9 AN: 3352

European-Non Finnish (NFE) AF: 0.00640 AC: 4972 AN: 777300

Other (OTH) AF: 0.00583 AC: 258 AN: 44262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000113 AC: 13 AN: 115168 Hom.: 0 Cov.: 29 AF XY: 0.0000907 AC XY: 5 AN XY: 55136

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000614 AC: 2 AN: 32550

American (AMR) AF: 0.0000891 AC: 1 AN: 11220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2750

East Asian (EAS) AF: 0.00 AC: 0 AN: 3810

South Asian (SAS) AF: 0.00 AC: 0 AN: 3326

European-Finnish (FIN) AF: 0.000320 AC: 2 AN: 6250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000151 AC: 8 AN: 52842

Other (OTH) AF: 0.00 AC: 0 AN: 1510

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000616216), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00333 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370370394; hg19: chr1-8022800;