3-183840614-C-T

Variant names:

• chr3-183840614-C-T
• rs3732581
• NM_018622.7:c.784G>A

Variant summary

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

The NM_018622.7(PARL):​c.784G>A​(p.Val262Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,400,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: PARL NM_018622.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 61 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=0.41108274).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018622.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARL	NM_018622.7	MANE Select	c.784G>A	p.Val262Met	missense	Exon 7 of 10	NP_061092.3
	PARL	NM_001324436.2		c.784G>A	p.Val262Met	missense	Exon 7 of 9	NP_001311365.1
	PARL	NM_001037639.3		c.634G>A	p.Val212Met	missense	Exon 6 of 9	NP_001032728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARL	ENST00000317096.9	TSL:1 MANE Select	c.784G>A	p.Val262Met	missense	Exon 7 of 10	ENSP00000325421.5
	ENSG00000283765	ENST00000639401.1	TSL:5	c.784G>A	p.Val262Met	missense	Exon 7 of 11	ENSP00000491227.1
	PARL	ENST00000311101.9	TSL:1	c.634G>A	p.Val212Met	missense	Exon 6 of 9	ENSP00000310676.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245198 AF XY: 0.00000755

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1400064 Hom.: 0 Cov.: 24 AF XY: 0.00000715 AC XY: 5 AN XY: 699056

African (AFR) AF: 0.00 AC: 0 AN: 32062

American (AMR) AF: 0.0000457 AC: 2 AN: 43726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39256

South Asian (SAS) AF: 0.00 AC: 0 AN: 81390

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00000283 AC: 3 AN: 1061278

Other (OTH) AF: 0.0000344 AC: 2 AN: 58180

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.074
Sift	Benign	0.050	D
Sift4G	Benign	0.067	T
Polyphen		0.14	B
Vest4		0.28
MutPred		0.43		Gain of glycosylation at T267 (P = 0.0702)
MVP		0.38
MPC		0.17
ClinPred		0.11	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.76
Mutation Taster		=84/16	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: rs3732581; hg19: chr3-183558402;