rs2305666

Positions:

• chr3-183833945-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018622.7(PARL):​c.829-120T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 731,038 control chromosomes in the GnomAD database, including 14,470 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (3014 hom., cov: 32)
  • Exomes 𝑓: 0.19 (11456 hom.)
• Consequence: PARL NM_018622.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.669

Genes affected

PARL (HGNC:18253): (presenilin associated rhomboid like) This gene encodes a member of the rhomboid family of intramembrane serine proteases that is localized to the inner mitochondrial membrane. The encoded protein regulates mitochondrial remodeling and apoptosis through regulated substrate proteolysis. Proteolytic processing of the encoded protein results in the release of a small peptide, P-beta, which may transit to the nucleus. Mutations in this gene may be associated with Parkinson's disease. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PARL	NM_018622.7	c.829-120T>G		intron_variant		ENST00000317096.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PARL	ENST00000317096.9	c.829-120T>G		intron_variant		1	NM_018622.7	P1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29159 AN: 152098 Hom.: 2993 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.187 AC: 107980 AN: 578822 Hom.: 11456 AF XY: 0.184 AC XY: 57309 AN XY: 311590

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.246

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.420

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.192 AC: 29216 AN: 152216 Hom.: 3014 Cov.: 32 AF XY: 0.191 AC XY: 14219 AN XY: 74420

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.429

Gnomad4 SAS AF: 0.153

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.193

Alfa AF: 0.182 Hom.: 1157

Bravo AF: 0.198

Asia WGS AF: 0.304 AC: 1056 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.7
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs2305666; hg19: chr3-183551733;