rs13091

Variant names:

• chr3-183842407-A-G
• rs13091
• NM_018622.7:c.648T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_018622.7(PARL):​c.648T>C​(p.His216His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,611,362 control chromosomes in the GnomAD database, including 183,246 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (17230 hom., cov: 32)
  • Exomes 𝑓: 0.47 (166016 hom.)
• Consequence: PARL NM_018622.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 22 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARL	NM_018622.7	MANE Select	c.648T>C	p.His216His	synonymous	Exon 6 of 10	NP_061092.3
	PARL	NM_001324436.2		c.648T>C	p.His216His	synonymous	Exon 6 of 9	NP_001311365.1
	PARL	NM_001324438.2		c.648T>C	p.His216His	synonymous	Exon 6 of 8	NP_001311367.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARL	ENST00000317096.9	TSL:1 MANE Select	c.648T>C	p.His216His	synonymous	Exon 6 of 10	ENSP00000325421.5	Q9H300-1
	ENSG00000283765	ENST00000639401.1	TSL:5	c.648T>C	p.His216His	synonymous	Exon 6 of 11	ENSP00000491227.1	A0A1W2PP11
	PARL	ENST00000311101.9	TSL:1	c.608-1767T>C		intron	N/A	ENSP00000310676.5	Q9H300-2

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71948 AN: 151984 Hom.: 17223 Cov.: 32

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.505

GnomAD2 exomes AF: 0.468 AC: 117604 AN: 251232 AF XY: 0.464

Gnomad AFR exome AF: 0.490

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.545

Gnomad EAS exome AF: 0.422

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.483

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.475 AC: 692821 AN: 1459260 Hom.: 166016 Cov.: 33 AF XY: 0.474 AC XY: 343841 AN XY: 726058

African (AFR) AF: 0.496 AC: 16567 AN: 33432

American (AMR) AF: 0.528 AC: 23631 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 14231 AN: 26122

East Asian (EAS) AF: 0.450 AC: 17847 AN: 39690

South Asian (SAS) AF: 0.426 AC: 36694 AN: 86202

European-Finnish (FIN) AF: 0.346 AC: 18459 AN: 53338

Middle Eastern (MID) AF: 0.607 AC: 3495 AN: 5760

European-Non Finnish (NFE) AF: 0.481 AC: 533303 AN: 1109688

Other (OTH) AF: 0.474 AC: 28594 AN: 60310

GnomAD4 genome AF: 0.473 AC: 71971 AN: 152102 Hom.: 17230 Cov.: 32 AF XY: 0.466 AC XY: 34681 AN XY: 74350

African (AFR) AF: 0.494 AC: 20468 AN: 41474

American (AMR) AF: 0.500 AC: 7639 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1922 AN: 3470

East Asian (EAS) AF: 0.420 AC: 2172 AN: 5174

South Asian (SAS) AF: 0.422 AC: 2040 AN: 4832

European-Finnish (FIN) AF: 0.327 AC: 3456 AN: 10584

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32779 AN: 67972

Other (OTH) AF: 0.499 AC: 1053 AN: 2112

Alfa AF: 0.489 Hom.: 7849

Bravo AF: 0.491

Asia WGS AF: 0.417 AC: 1454 AN: 3478

EpiCase AF: 0.498

EpiControl AF: 0.500

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.9
DANN	Benign	0.55
PhyloP100		1.2
PromoterAI		0.0083	Neutral
Mutation Taster		=97/3	polymorphism (auto)

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: rs13091; hg19: chr3-183560195; COSMIC: COSV57699961; COSMIC: COSV57699961;