3-183868095-A-G

Variant names:

• chr3-183868095-A-G
• rs953419
• NM_018622.7:c.126-35T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018622.7(PARL):​c.126-35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,487,720 control chromosomes in the GnomAD database, including 34,617 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 0.23 (4229 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30388 hom.)
• Consequence: PARL NM_018622.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARL	NM_018622.7	MANE Select	c.126-35T>C		intron	N/A	NP_061092.3
	PARL	NM_001324436.2		c.126-35T>C		intron	N/A	NP_001311365.1
	PARL	NM_001037639.3		c.126-35T>C		intron	N/A	NP_001032728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARL	ENST00000317096.9	TSL:1 MANE Select	c.126-35T>C		intron	N/A	ENSP00000325421.5
	ENSG00000283765	ENST00000639401.1	TSL:5	c.126-35T>C		intron	N/A	ENSP00000491227.1
	PARL	ENST00000311101.9	TSL:1	c.126-35T>C		intron	N/A	ENSP00000310676.5

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34626 AN: 151962 Hom.: 4197 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.241 AC: 60051 AN: 249552 AF XY: 0.238

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.449

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.204 AC: 272696 AN: 1335640 Hom.: 30388 Cov.: 21 AF XY: 0.205 AC XY: 137906 AN XY: 671420

African (AFR) AF: 0.253 AC: 7848 AN: 31022

American (AMR) AF: 0.284 AC: 12621 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5540 AN: 25370

East Asian (EAS) AF: 0.456 AC: 17821 AN: 39084

South Asian (SAS) AF: 0.278 AC: 23252 AN: 83758

European-Finnish (FIN) AF: 0.229 AC: 12136 AN: 52970

Middle Eastern (MID) AF: 0.186 AC: 1027 AN: 5514

European-Non Finnish (NFE) AF: 0.181 AC: 180100 AN: 997188

Other (OTH) AF: 0.220 AC: 12351 AN: 56236

GnomAD4 genome AF: 0.228 AC: 34715 AN: 152080 Hom.: 4229 Cov.: 32 AF XY: 0.231 AC XY: 17151 AN XY: 74338

African (AFR) AF: 0.251 AC: 10417 AN: 41480

American (AMR) AF: 0.264 AC: 4041 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 754 AN: 3470

East Asian (EAS) AF: 0.452 AC: 2328 AN: 5146

South Asian (SAS) AF: 0.285 AC: 1375 AN: 4824

European-Finnish (FIN) AF: 0.231 AC: 2446 AN: 10570

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12498 AN: 67998

Other (OTH) AF: 0.234 AC: 493 AN: 2110

Alfa AF: 0.200 Hom.: 14325

Bravo AF: 0.231

Asia WGS AF: 0.404 AC: 1404 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.5
DANN	Benign	0.31
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs953419; hg19: chr3-183585883; COSMIC: COSV57702914;