Variant 3-183840614-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.47 ( 17205 hom., cov: 32)

Exomes 𝑓: 0.47 ( 154318 hom. )

Consequence

PARL
NM_018622.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.08

Variant links:

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]

PARL links:

ENSG00000283765 (HGNC:):

ENSG00000283765 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
PARL	NM_018622.7 link	c.784G>C	p.Val262Leu	missense_variant	7/10	ENST00000317096.9	NP_061092.3	Q9H300-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARL	ENST00000317096.9 link	c.784G>C	p.Val262Leu	missense_variant	7/10	1	NM_018622.7	ENSP00000325421.5		Q9H300-1
ENSG00000283765	ENST00000639401.1 link	c.784G>C	p.Val262Leu	missense_variant	7/11	5		ENSP00000491227.1		A0A1W2PP11

Frequencies

GnomAD3 genomes

AF:

0.474

AC:

71852

AN:

151736

Hom.:

17199

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.465

AC:

113926

AN:

245198

Hom.:

27082

AF XY:

0.461

AC XY:

61022

AN XY:

132390

show subpopulations

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 SAS exome

AF:

0.412

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.:

AF XY:

0.467

AC XY:

324034

AN XY:

694320

show subpopulations

Gnomad4 AFR exome

AF:

0.490

Gnomad4 AMR exome

AF:

0.525

Gnomad4 ASJ exome

AF:

0.542

Gnomad4 EAS exome

AF:

0.450

Gnomad4 SAS exome

AF:

0.415

Gnomad4 FIN exome

AF:

0.343

Gnomad4 NFE exome

AF:

0.473

Gnomad4 OTH exome

AF:

0.467

GnomAD4 genome

AF:

0.473

AC:

71871

AN:

151848

Hom.:

17205

Cov.:

AF XY:

0.467

AC XY:

34614

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.494

Gnomad4 AMR

AF:

0.500

Gnomad4 ASJ

AF:

0.553

Gnomad4 EAS

AF:

0.420

Gnomad4 SAS

AF:

0.421

Gnomad4 FIN

AF:

0.325

Gnomad4 NFE

AF:

0.482

Gnomad4 OTH

AF:

0.498

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

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.023

.;.;T;.;.;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.95

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

MutationAssessor

Benign

-0.10

.;.;N;.;.;.

PrimateAI

Uncertain

0.61

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

GERP RS

2.3

Varity_R

0.043

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over