Genetic Variant PARL:p.Asp141Ala (chr3-183866665-T-G) – 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>C(p.Asp141Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PARL
NM_018622.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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>C	p.Asp141Ala	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>C	p.Asp141Ala	missense_variant	Exon 3 of 10	1	NM_018622.7	ENSP00000325421.5		Q9H300-1
ENSG00000283765	ENST00000639401.1 link	c.422A>C	p.Asp141Ala	missense_variant	Exon 3 of 11	5		ENSP00000491227.1		A0A1W2PP11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459852

Hom.:

Cov.:

AF XY:

0.00000275

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:

0.00

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: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.422A>C (p.D141A) alteration is located in exon 3 (coding exon 3) of the PARL gene. This alteration results from a A to C substitution at nucleotide position 422, causing the aspartic acid (D) at amino acid position 141 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;T;.;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.070

MetaRNN

Uncertain

0.60

D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.3

.;M;M;.

PhyloP100

7.4

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.0

.;D;D;D

REVEL

Uncertain

0.49

Sift

Benign

0.030

.;D;D;D

Sift4G

Benign

0.063

.;T;T;T

Polyphen

0.073, 1.0

.;B;D;.

Vest4

0.58, 0.67, 0.58

MutPred

0.45

Gain of glycosylation at S142 (P = 0.0495);Gain of glycosylation at S142 (P = 0.0495);Gain of glycosylation at S142 (P = 0.0495);Gain of glycosylation at S142 (P = 0.0495);

MVP

0.84

MPC

0.21

ClinPred

0.97

GERP RS

5.3

Varity_R

0.23

gMVP

0.76

Mutation Taster

=50/50

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over