rs3734464

Variant names:

• chr6-161348803-T-C
• rs3734464
• NM_004562.3:c.*1296A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004562.3(PRKN):​c.*1296A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0816 in 210,028 control chromosomes in the GnomAD database, including 763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.082 (557 hom., cov: 32)
  • Exomes 𝑓: 0.080 (206 hom.)
• Consequence: PRKN NM_004562.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.08
• Publications: 10 publications found

Genes affected

PRKN (HGNC:8607): (parkin RBR E3 ubiquitin protein ligase) The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

PRKN Gene-Disease associations (from GenCC):

• autosomal recessive juvenile Parkinson disease 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-161348803-T-C is Benign according to our data. Variant chr6-161348803-T-C is described in ClinVar as Benign. ClinVar VariationId is 355998.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004562.3. 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
	PRKN	NM_004562.3	MANE Select	c.*1296A>G		3_prime_UTR	Exon 12 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.*1296A>G		3_prime_UTR	Exon 11 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.*1296A>G		3_prime_UTR	Exon 9 of 9	NP_054643.2	O60260-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	ENST00000366898.6	TSL:1 MANE Select	c.*1296A>G		3_prime_UTR	Exon 12 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.*1296A>G		3_prime_UTR	Exon 11 of 11	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.*1296A>G		3_prime_UTR	Exon 9 of 9	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 12525 AN: 152190 Hom.: 556 Cov.: 32

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.0772

Gnomad FIN AF: 0.0884

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0923

GnomAD4 exome AF: 0.0796 AC: 4596 AN: 57720 Hom.: 206 Cov.: 0 AF XY: 0.0807 AC XY: 2161 AN XY: 26794

African (AFR) AF: 0.0554 AC: 140 AN: 2526

American (AMR) AF: 0.0594 AC: 99 AN: 1668

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 412 AN: 3676

East Asian (EAS) AF: 0.0220 AC: 195 AN: 8870

South Asian (SAS) AF: 0.0784 AC: 40 AN: 510

European-Finnish (FIN) AF: 0.105 AC: 4 AN: 38

Middle Eastern (MID) AF: 0.0801 AC: 29 AN: 362

European-Non Finnish (NFE) AF: 0.0937 AC: 3307 AN: 35302

Other (OTH) AF: 0.0776 AC: 370 AN: 4768

GnomAD4 genome AF: 0.0823 AC: 12542 AN: 152308 Hom.: 557 Cov.: 32 AF XY: 0.0805 AC XY: 5996 AN XY: 74478

African (AFR) AF: 0.0603 AC: 2506 AN: 41578

American (AMR) AF: 0.0710 AC: 1086 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3470

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5180

South Asian (SAS) AF: 0.0769 AC: 371 AN: 4826

European-Finnish (FIN) AF: 0.0884 AC: 938 AN: 10614

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6846 AN: 68016

Other (OTH) AF: 0.0947 AC: 200 AN: 2112

Alfa AF: 0.0928 Hom.: 1144

Bravo AF: 0.0776

Asia WGS AF: 0.0550 AC: 189 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive juvenile Parkinson disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.064
DANN	Benign	0.36
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs3734464; hg19: chr6-161769835; COSMIC: COSV58210349; COSMIC: COSV58210349;