3-183842387-G-C

Variant names:

• chr3-183842387-G-C
• rs536646854
• NM_018622.7:c.668C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018622.7(PARL):​c.668C>G​(p.Ala223Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A223V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PARL NM_018622.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.90
• Publications: 0 publications found

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]

ENSG00000283765 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32109928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARL	NM_018622.7	c.668C>G	p.Ala223Gly	missense_variant	Exon 6 of 10	ENST00000317096.9	NP_061092.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARL	ENST00000317096.9	c.668C>G	p.Ala223Gly	missense_variant	Exon 6 of 10	1	NM_018622.7	ENSP00000325421.5
ENSG00000283765	ENST00000639401.1	c.668C>G	p.Ala223Gly	missense_variant	Exon 6 of 11	5		ENSP00000491227.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460912 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726840

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111176

Other (OTH) AF: 0.0000166 AC: 1 AN: 60344

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	.;.;T;.
Eigen	Benign	0.023
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.73	.;.;N;.
PhyloP100		4.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	.;.;D;D
REVEL	Benign	0.12
Sift	Benign	0.16	.;.;T;T
Sift4G	Benign	0.48	.;.;T;T
Polyphen		0.017	.;.;B;.
Vest4		0.68
MutPred		0.52		Loss of catalytic residue at A223 (P = 0.097);.;Loss of catalytic residue at A223 (P = 0.097);.;
MVP		0.70
MPC		0.14
ClinPred		0.62	D
GERP RS		4.4
PromoterAI		-0.014	Neutral
Varity_R		0.18
gMVP		0.73
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs536646854; hg19: chr3-183560175;