chr3-183862779-A-G

Position:

• chr3-183862779-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018622.7(PARL):​c.485T>C​(p.Leu162Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PARL NM_018622.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARL	NM_018622.7	c.485T>C	p.Leu162Pro	missense_variant	4/10	ENST00000317096.9	NP_061092.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARL	ENST00000317096.9	c.485T>C	p.Leu162Pro	missense_variant	4/10	1	NM_018622.7	ENSP00000325421	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.485T>C (p.L162P) alteration is located in exon 4 (coding exon 4) of the PARL gene. This alteration results from a T to C substitution at nucleotide position 485, causing the leucine (L) at amino acid position 162 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	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	.;D;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.8	.;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.8	.;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.97, 0.97, 0.97
MutPred		0.68		Loss of stability (P = 0.0105);Loss of stability (P = 0.0105);Loss of stability (P = 0.0105);Loss of stability (P = 0.0105);
MVP		0.96
MPC		0.59
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-183580567;