3-183844245-G-A

Variant names:

Variant summary

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

The NM_018622.7(PARL):c.593C>T(p.Ser198Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000451 in 1,596,204 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PARL
NM_018622.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.45

Publications

2 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.593C>T	p.Ser198Leu	missense_variant	Exon 5 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.593C>T	p.Ser198Leu	missense_variant	Exon 5 of 10	1	NM_018622.7	ENSP00000325421.5		Q9H300-1
ENSG00000283765	ENST00000639401.1 link	c.593C>T	p.Ser198Leu	missense_variant	Exon 5 of 11	5		ENSP00000491227.1		A0A1W2PP11

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251350

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000436

AC:

AN:

1444074

Hom.:

Cov.:

AF XY:

0.0000514

AC XY:

AN XY:

719638

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33142

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39588

South Asian (SAS)

AF:

0.00

AC:

AN:

85900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4666

European-Non Finnish (NFE)

AF:

0.0000538

AC:

AN:

1096936

Other (OTH)

AF:

0.0000335

AC:

AN:

59694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.593C>T (p.S198L) alteration is located in exon 5 (coding exon 5) of the PARL gene. This alteration results from a C to T substitution at nucleotide position 593, causing the serine (S) at amino acid position 198 to be replaced by a leucine (L). 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

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

.;.;T;.;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.73

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

2.9

.;.;M;M;.

PhyloP100

9.4

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.0

.;.;D;D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

.;.;D;D;D

Sift4G

Uncertain

0.0030

.;.;D;D;D

Polyphen

0.28, 1.0

.;.;B;D;.

Vest4

0.78, 0.84, 0.84

MutPred

0.52

Gain of glycosylation at T197 (P = 0.0232);.;Gain of glycosylation at T197 (P = 0.0232);Gain of glycosylation at T197 (P = 0.0232);Gain of glycosylation at T197 (P = 0.0232);

MVP

0.71

MPC

0.16

ClinPred

0.97

GERP RS

5.4

PromoterAI

-0.048

Neutral

(source)

Varity_R

0.68

gMVP

0.81

Mutation Taster

=15/85

disease causing

(source)

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

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3-183844245-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over