3-183868095-A-G

Variant names:

• chr3-183868095-A-G
• rs953419
• NM_018622.7:c.126-35T>C

Variant summary

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

The NM_018622.7(PARL):​c.126-35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,487,720 control chromosomes in the GnomAD database, including 34,617 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 0.23 (4229 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30388 hom.)
• Consequence: PARL NM_018622.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272

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]

ENSG00000283765 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARL	NM_018622.7	c.126-35T>C		intron_variant	Intron 1 of 9	ENST00000317096.9	NP_061092.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARL	ENST00000317096.9	c.126-35T>C		intron_variant	Intron 1 of 9	1	NM_018622.7	ENSP00000325421.5
ENSG00000283765	ENST00000639401.1	c.126-35T>C		intron_variant	Intron 1 of 10	5		ENSP00000491227.1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34626 AN: 151962 Hom.: 4197 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.241 AC: 60051 AN: 249552 Hom.: 7990 AF XY: 0.238 AC XY: 32092 AN XY: 134992

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.449

Gnomad SAS exome AF: 0.286

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.204 AC: 272696 AN: 1335640 Hom.: 30388 Cov.: 21 AF XY: 0.205 AC XY: 137906 AN XY: 671420

Gnomad4 AFR exome AF: 0.253

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.456

Gnomad4 SAS exome AF: 0.278

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.228 AC: 34715 AN: 152080 Hom.: 4229 Cov.: 32 AF XY: 0.231 AC XY: 17151 AN XY: 74338

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.452

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.234

Alfa AF: 0.195 Hom.: 6683

Bravo AF: 0.231

Asia WGS AF: 0.404 AC: 1404 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.5
DANN	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs953419; hg19: chr3-183585883; COSMIC: COSV57702914;