1-7962740-CTTTTTTTT-CTTTTT

Variant names:

• chr1-7962740-CTTT-C
• rs370370394
• NM_007262.5:c.-23-6_-23-4delTTT

Variant summary

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

The NM_007262.5(PARK7):​c.-23-6_-23-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,143,316 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0028 (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 AFR (0.0037) population. However there is too low homozygotes in high coverage region: (expected more than 1, 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.-23-6_-23-4delTTT		splice_region intron	N/A	NP_009193.2
	PARK7	NM_001123377.2		c.-23-6_-23-4delTTT		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.-23-6_-23-4delTTT		splice_region intron	N/A	ENSP00000340278.5	Q99497
	PARK7	ENST00000493678.5	TSL:1	c.-23-6_-23-4delTTT		splice_region intron	N/A	ENSP00000418770.1	Q99497
	PARK7	ENST00000872631.1		c.-29_-27delTTT		5_prime_UTR	Exon 1 of 6	ENSP00000542690.1

Frequencies

GnomAD3 genomes AF: 0.0000347 AC: 4 AN: 115188 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000299

Gnomad FIN AF: 0.000160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00427 AC: 384 AN: 89970 AF XY: 0.00443

Gnomad AFR exome AF: 0.00828

Gnomad AMR exome AF: 0.00530

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00350

Gnomad FIN exome AF: 0.00443

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.00462

GnomAD4 exome AF: 0.00278 AC: 2857 AN: 1028128 Hom.: 0 AF XY: 0.00272 AC XY: 1417 AN XY: 520616

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

African (AFR) AF: 0.00440 AC: 98 AN: 22266

American (AMR) AF: 0.00378 AC: 104 AN: 27526

Ashkenazi Jewish (ASJ) AF: 0.00269 AC: 55 AN: 20412

East Asian (EAS) AF: 0.00278 AC: 90 AN: 32432

South Asian (SAS) AF: 0.00168 AC: 110 AN: 65622

European-Finnish (FIN) AF: 0.00336 AC: 118 AN: 35090

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

European-Non Finnish (NFE) AF: 0.00274 AC: 2127 AN: 777160

Other (OTH) AF: 0.00330 AC: 146 AN: 44268

⚠️ 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: 0.0000347 AC: 4 AN: 115188 Hom.: 0 Cov.: 29 AF XY: 0.0000544 AC XY: 3 AN XY: 55130

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

African (AFR) AF: 0.0000308 AC: 1 AN: 32514

American (AMR) AF: 0.00 AC: 0 AN: 11222

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3822

South Asian (SAS) AF: 0.000299 AC: 1 AN: 3346

European-Finnish (FIN) AF: 0.000160 AC: 1 AN: 6246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52850

Other (OTH) AF: 0.00 AC: 0 AN: 1506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000521060), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00166 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs370370394; hg19: chr1-8022800;