Genetic Variant PLIN1:p.Lys520Arg (chr15-89665593-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002666.5(PLIN1):c.1559A>G(p.Lys520Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000727 in 1,375,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

PLIN1
NM_002666.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.78

Publications

0 publications found

Variant links:

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]

PLIN1 Gene-Disease associations (from GenCC):

PLIN1-related familial partial lipodystrophy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, Ambry Genetics

PLIN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3116799).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002666.5. 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
	PLIN1	NM_002666.5	MANE Select	c.1559A>G	p.Lys520Arg	missense	Exon 9 of 9	NP_002657.3	O60240
	PLIN1	NM_001145311.2		c.1559A>G	p.Lys520Arg	missense	Exon 9 of 9	NP_001138783.1	O60240

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLIN1	ENST00000300055.10	TSL:1 MANE Select	c.1559A>G	p.Lys520Arg	missense	Exon 9 of 9	ENSP00000300055.5	O60240
PLIN1	ENST00000896664.1		c.1667A>G	p.Lys556Arg	missense	Exon 9 of 9	ENSP00000566723.1
PLIN1	ENST00000896666.1		c.1589A>G	p.Lys530Arg	missense	Exon 9 of 9	ENSP00000566725.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1375238

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678828

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30424

American (AMR)

AF:

0.00

AC:

AN:

35062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24840

East Asian (EAS)

AF:

0.00

AC:

AN:

34508

South Asian (SAS)

AF:

0.00

AC:

AN:

78126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4028

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1070896

Other (OTH)

AF:

0.00

AC:

AN:

56902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

PLIN1-related familial partial lipodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.65

M_CAP

Benign

0.033

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.1

PhyloP100

3.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.49

REVEL

Benign

0.057

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.25

MutPred

0.18

Loss of methylation at K520 (P = 0.0161)

MVP

0.24

MPC

2.2

ClinPred

0.98

GERP RS

5.1

Varity_R

0.41

gMVP

0.022

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over