rs111663599

chr15-89670112-C-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.466G>T(p.Val156Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,614,048 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (23 hom., cov: 32)
  • Exomes 𝑓: 0.011 (176 hom.)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.219

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=0.0034962893).
• BP6: Variant 15-89670112-C-A is Benign according to our data. Variant chr15-89670112-C-A is described in ClinVar as [Benign]. Clinvar id is 393439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89670112-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1583/152340) while in subpopulation NFE AF= 0.0122 (828/68026). AF 95% confidence interval is 0.0115. There are 23 homozygotes in gnomad4. There are 902 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1585 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLIN1	NM_002666.5	c.466G>T	p.Val156Leu	missense_variant	5/9	ENST00000300055.10
PLIN1	NM_001145311.2	c.466G>T	p.Val156Leu	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLIN1	ENST00000300055.10	c.466G>T	p.Val156Leu	missense_variant	5/9	1	NM_002666.5	P1
PLIN1	ENST00000430628.2	c.466G>T	p.Val156Leu	missense_variant	5/9	5		P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1585 AN: 152222 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0531

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.0125 AC: 3136 AN: 250760 Hom.: 51 AF XY: 0.0125 AC XY: 1701 AN XY: 135592

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000818

Gnomad FIN exome AF: 0.0518

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0110 AC: 16084 AN: 1461708 Hom.: 176 Cov.: 35 AF XY: 0.0107 AC XY: 7764 AN XY: 727142

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.0538

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.00972

GnomAD4 genome AF: 0.0104 AC: 1583 AN: 152340 Hom.: 23 Cov.: 32 AF XY: 0.0121 AC XY: 902 AN XY: 74486

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0531

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.0113 Hom.: 16

Bravo AF: 0.00691

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.0110 AC: 95

ExAC AF: 0.0134 AC: 1622

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Feb 01, 2019

ACMG criteria: BP4 (REVEL 0.046 + 8 predictors), not using PP3 (2 predictors)), BA1 (5.3% in gnomAD EF, MAF 1.5% overall), BS2 (204 cases and 197 controls in type2diabetesgenetics.org)= benign -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

PLIN1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	13
Dann	Benign	0.97
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.073	N
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.046
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.095	B;B
Vest4		0.090
MutPred		0.67		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MPC		0.028
ClinPred		0.011	T
GERP RS		0.41
Varity_R		0.10
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs111663599; hg19: chr15-90213343; COSMIC: COSV55584816; COSMIC: COSV55584816;