rs114583540

chr15-89669579-C-Achr15-89669579-C-T

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.692G>T(p.Arg231Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,954 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (15 hom., cov: 31)
  • Exomes 𝑓: 0.00076 (17 hom.)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.46

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=0.01785186).
• BP6: Variant 15-89669579-C-A is Benign according to our data. Variant chr15-89669579-C-A is described in ClinVar as [Benign]. Clinvar id is 393438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89669579-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0077 (1172/152226) while in subpopulation AFR AF= 0.0267 (1108/41530). AF 95% confidence interval is 0.0254. There are 15 homozygotes in gnomad4. There are 553 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLIN1	NM_002666.5	c.692G>T	p.Arg231Leu	missense_variant	6/9	ENST00000300055.10
PLIN1	NM_001145311.2	c.692G>T	p.Arg231Leu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLIN1	ENST00000300055.10	c.692G>T	p.Arg231Leu	missense_variant	6/9	1	NM_002666.5	P1
PLIN1	ENST00000430628.2	c.692G>T	p.Arg231Leu	missense_variant	6/9	5		P1

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1169 AN: 152108 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00189 AC: 475 AN: 251272 Hom.: 6 AF XY: 0.00138 AC XY: 187 AN XY: 135836

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000762 AC: 1114 AN: 1461728 Hom.: 17 Cov.: 33 AF XY: 0.000715 AC XY: 520 AN XY: 727166

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00770 AC: 1172 AN: 152226 Hom.: 15 Cov.: 31 AF XY: 0.00743 AC XY: 553 AN XY: 74430

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00161 Hom.: 4

Bravo AF: 0.00847

ESP6500AA AF: 0.0255 AC: 112

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00244 AC: 296

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

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 08, 2019

ACMG criteria: BP4 (REVEL 0.073 + 7 predictors), BP5 (found in case with alternate cause), BA1 (2.5% MAF in gnomAD African)= benign -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	2.5
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.073
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.041	D;D
Polyphen		0.76	P;P
Vest4		0.41
MVP		0.055
MPC		0.059
ClinPred		0.053	T
GERP RS		-4.7
Varity_R		0.23
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -14

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

Publications

LitVar

Other links and lift over

dbSNP: rs114583540; hg19: chr15-90212810;