Genetic Variant PARL:p.Asp141Gly (chr3-183866665-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018622.7(PARL):c.422A>G(p.Asp141Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,852 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D141A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PARL
NM_018622.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.38

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARL	NM_018622.7 link	c.422A>G	p.Asp141Gly	missense_variant	Exon 3 of 10	ENST00000317096.9	NP_061092.3	Q9H300-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARL	ENST00000317096.9 link	c.422A>G	p.Asp141Gly	missense_variant	Exon 3 of 10	1	NM_018622.7	ENSP00000325421.5		Q9H300-1
ENSG00000283765	ENST00000639401.1 link	c.422A>G	p.Asp141Gly	missense_variant	Exon 3 of 11	5		ENSP00000491227.1		A0A1W2PP11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251316

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459852

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111374

Other (OTH)

AF:

0.00

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;T;.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.59

D;D;D;D

MetaSVM

Uncertain

-0.092

MutationAssessor

Uncertain

2.3

.;M;M;.

PhyloP100

7.4

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.8

.;D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.022

.;D;D;D

Sift4G

Uncertain

0.038

.;D;D;D

Polyphen

0.46, 0.99

.;P;D;.

Vest4

0.67, 0.73, 0.64

MutPred

0.39

Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);

MVP

0.83

MPC

0.19

ClinPred

0.93

GERP RS

5.3

Varity_R

0.30

gMVP

0.76

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr3-183866665-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over