rs3732581

Variant names:

• chr3-183840614-C-G
• rs3732581
• NM_018622.7:c.784G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-183840614-C-G
• chr3-183840614-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018622.7(PARL):​c.784G>C​(p.Val262Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 1,542,024 control chromosomes in the GnomAD database, including 171,523 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (17205 hom., cov: 32)
  • Exomes 𝑓: 0.47 (154318 hom.)
• Consequence: PARL NM_018622.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 61 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.5492376E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARL	NM_018622.7	c.784G>C	p.Val262Leu	missense_variant	Exon 7 of 10	ENST00000317096.9	NP_061092.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARL	ENST00000317096.9	c.784G>C	p.Val262Leu	missense_variant	Exon 7 of 10	1	NM_018622.7	ENSP00000325421.5
ENSG00000283765	ENST00000639401.1	c.784G>C	p.Val262Leu	missense_variant	Exon 7 of 11	5		ENSP00000491227.1

Frequencies

GnomAD3 genomes AF: 0.474 AC: 71852 AN: 151736 Hom.: 17199 Cov.: 32

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.594

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.504

GnomAD2 exomes AF: 0.465 AC: 113926 AN: 245198 AF XY: 0.461

Gnomad AFR exome AF: 0.488

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.544

Gnomad EAS exome AF: 0.421

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.467 AC: 649665 AN: 1390176 Hom.: 154318 Cov.: 24 AF XY: 0.467 AC XY: 324034 AN XY: 694320

African (AFR) AF: 0.490 AC: 15602 AN: 31872

American (AMR) AF: 0.525 AC: 22886 AN: 43596

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 13782 AN: 25444

East Asian (EAS) AF: 0.450 AC: 17618 AN: 39182

South Asian (SAS) AF: 0.415 AC: 33595 AN: 80988

European-Finnish (FIN) AF: 0.343 AC: 18183 AN: 52964

Middle Eastern (MID) AF: 0.599 AC: 3338 AN: 5568

European-Non Finnish (NFE) AF: 0.473 AC: 497644 AN: 1052758

Other (OTH) AF: 0.467 AC: 27017 AN: 57804

GnomAD4 genome AF: 0.473 AC: 71871 AN: 151848 Hom.: 17205 Cov.: 32 AF XY: 0.467 AC XY: 34614 AN XY: 74194

African (AFR) AF: 0.494 AC: 20458 AN: 41398

American (AMR) AF: 0.500 AC: 7630 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1917 AN: 3468

East Asian (EAS) AF: 0.420 AC: 2168 AN: 5158

South Asian (SAS) AF: 0.421 AC: 2027 AN: 4818

European-Finnish (FIN) AF: 0.325 AC: 3411 AN: 10490

Middle Eastern (MID) AF: 0.587 AC: 169 AN: 288

European-Non Finnish (NFE) AF: 0.482 AC: 32769 AN: 67954

Other (OTH) AF: 0.498 AC: 1049 AN: 2108

Alfa AF: 0.488 Hom.: 13798

Bravo AF: 0.491

TwinsUK AF: 0.477 AC: 1768

ALSPAC AF: 0.495 AC: 1907

ESP6500AA AF: 0.492 AC: 2166

ESP6500EA AF: 0.484 AC: 4161

ExAC AF: 0.467 AC: 56698

Asia WGS AF: 0.416 AC: 1448 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.023	.;.;T;.;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
MetaRNN	Benign	0.000045	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.10	.;.;N;.;.;.
PhyloP100		1.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.79	.;.;N;N;N;N
REVEL	Benign	0.063
Sift	Benign	0.51	.;.;T;T;T;T
Sift4G	Benign	0.49	.;.;T;T;T;T
Polyphen		0.0020, 0.19	.;.;B;.;B;.
Vest4		0.21, 0.17, 0.13
MutPred		0.22		Loss of catalytic residue at V262 (P = 0.0258);.;Loss of catalytic residue at V262 (P = 0.0258);.;.;.;
MPC		0.14
ClinPred		0.0057	T
GERP RS		2.3
Varity_R		0.043
gMVP		0.78
Mutation Taster		=92/8	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: rs3732581; hg19: chr3-183558402; COSMIC: COSV57700167;