rs150004289

Positions:

• chr15-89673215-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002666.5(PLIN1):​c.245C>T​(p.Thr82Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00228 in 1,563,422 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.73

Genes affected

PLIN1 (HGNC:9076): (perilipin 1) The protein encoded by this gene coats lipid storage droplets in adipocytes, thereby protecting them until they can be broken down by hormone-sensitive lipase. The encoded protein is the major cAMP-dependent protein kinase substrate in adipocytes and, when unphosphorylated, may play a role in the inhibition of lipolysis. Alternatively spliced transcript variants varying in the 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02043277).
• BP6: Variant 15-89673215-G-A is Benign according to our data. Variant chr15-89673215-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 393440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89673215-G-A is described in Lovd as [Likely_benign]. Variant chr15-89673215-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00153 (233/152256) while in subpopulation NFE AF= 0.00253 (172/68016). AF 95% confidence interval is 0.00222. There are 2 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLIN1	NM_002666.5	c.245C>T	p.Thr82Ile	missense_variant	3/9	ENST00000300055.10	NP_002657.3
PLIN1	NM_001145311.2	c.245C>T	p.Thr82Ile	missense_variant	3/9		NP_001138783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLIN1	ENST00000300055.10	c.245C>T	p.Thr82Ile	missense_variant	3/9	1	NM_002666.5	ENSP00000300055.5
PLIN1	ENST00000430628.2	c.245C>T	p.Thr82Ile	missense_variant	3/9	5		ENSP00000402167.2

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152138 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00138 AC: 243 AN: 175882 Hom.: 0 AF XY: 0.00155 AC XY: 145 AN XY: 93812

Gnomad AFR exome AF: 0.000291

Gnomad AMR exome AF: 0.00112

Gnomad ASJ exome AF: 0.00136

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000124

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00236 AC: 3330 AN: 1411166 Hom.: 5 Cov.: 32 AF XY: 0.00226 AC XY: 1576 AN XY: 697590

Gnomad4 AFR exome AF: 0.000311

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.00194

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000264

Gnomad4 NFE exome AF: 0.00283

Gnomad4 OTH exome AF: 0.00213

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152256 Hom.: 2 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74438

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00231 Hom.: 2

Bravo AF: 0.00153

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00292 AC: 25

ExAC AF: 0.000639 AC: 76

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

May 17, 2016

ACMG Criteria: PP3, BS1 (ExAC), BS2 (ExAC), BP4 -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

PLIN1: BS1 -

PLIN1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.075	T;T
Polyphen		1.0	D;D
Vest4		0.47
MVP		0.26
MPC		0.20
ClinPred		0.043	T
GERP RS		5.3
Varity_R		0.16
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150004289; hg19: chr15-90216446;