3-183833513-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018622.7(PARL):​c.1007T>C​(p.Leu336Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PARL
NM_018622.7 missense

Scores

14
3
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

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]

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PARLNM_018622.7 linkc.1007T>C p.Leu336Pro missense_variant Exon 9 of 10 ENST00000317096.9 NP_061092.3 Q9H300-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PARLENST00000317096.9 linkc.1007T>C p.Leu336Pro missense_variant Exon 9 of 10 1 NM_018622.7 ENSP00000325421.5 Q9H300-1
ENSG00000283765ENST00000639401.1 linkc.1007T>C p.Leu336Pro missense_variant Exon 9 of 11 5 ENSP00000491227.1 A0A1W2PP11

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459616
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726298
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33428
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39688
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86238
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5752
European-Non Finnish (NFE)
AF:
9.01e-7
AC:
1
AN:
1109940
Other (OTH)
AF:
0.00
AC:
0
AN:
60302
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 08, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1007T>C (p.L336P) alteration is located in exon 9 (coding exon 9) of the PARL gene. This alteration results from a T to C substitution at nucleotide position 1007, causing the leucine (L) at amino acid position 336 to be replaced by a proline (P). 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
1.0
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.38
.;.;T;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.89
D;D;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Pathogenic
4.2
.;.;H;.;.
PhyloP100
9.3
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-6.7
.;.;D;D;D
REVEL
Pathogenic
0.75
Sift
Pathogenic
0.0
.;.;D;D;D
Sift4G
Pathogenic
0.0010
.;.;D;D;D
Polyphen
1.0
.;.;D;D;.
Vest4
0.99, 0.99
MutPred
0.90
Loss of stability (P = 0.0979);.;Loss of stability (P = 0.0979);.;.;
MVP
0.87
MPC
0.79
ClinPred
1.0
D
GERP RS
5.6
Varity_R
1.0
gMVP
0.99
Mutation Taster
=5/95
disease causing

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

Other links and lift over

dbSNP: rs1728193494; hg19: chr3-183551301; API