15-89665767-G-A

Position:

chr15-89665767-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_002666.5(PLIN1):c.1385C>T(p.Pro462Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,274,976 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

PLIN1
NM_002666.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.260

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013460368).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000205 (31/150904) while in subpopulation SAS AF= 0.00083 (4/4818). AF 95% confidence interval is 0.000283. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLIN1	NM_002666.5 linkuse as main transcript	c.1385C>T	p.Pro462Leu	missense_variant	9/9	ENST00000300055.10	NP_002657.3	O60240
PLIN1	NM_001145311.2 linkuse as main transcript	c.1385C>T	p.Pro462Leu	missense_variant	9/9		NP_001138783.1	O60240

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PLIN1	ENST00000300055.10 linkuse as main transcript	c.1385C>T	p.Pro462Leu	missense_variant	9/9	1	NM_002666.5	ENSP00000300055.5	O60240
PLIN1	ENST00000430628.2 linkuse as main transcript	c.1385C>T	p.Pro462Leu	missense_variant	9/9	5		ENSP00000402167.2	O60240
PLIN1	ENST00000560330.1 linkuse as main transcript	c.124-826C>T		intron_variant		5		ENSP00000453426.1	H0YM16

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

150794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.000200

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000355

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000421

AC:

AN:

2378

Hom.:

AF XY:

0.000628

AC XY:

AN XY:

1592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000620

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000314

AC:

353

AN:

1124072

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

182

AN XY:

541366

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000211

Gnomad4 EAS exome

AF:

0.0000391

Gnomad4 SAS exome

AF:

0.000887

Gnomad4 FIN exome

AF:

0.00108

Gnomad4 NFE exome

AF:

0.000299

Gnomad4 OTH exome

AF:

0.000223

GnomAD4 genome

AF:

0.000205

AC:

AN:

150904

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

73744

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000200

Gnomad4 NFE

AF:

0.000355

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.000318

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.1385C>T (p.P462L) alteration is located in exon 9 (coding exon 8) of the PLIN1 gene. This alteration results from a C to T substitution at nucleotide position 1385, causing the proline (P) at amino acid position 462 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.72

CADD

Benign

4.4

DANN

Benign

0.95

DEOGEN2

Benign

0.087

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.44

.;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.51

N;N

REVEL

Benign

0.026

Sift

Benign

0.80

T;T

Sift4G

Benign

0.90

T;T

Polyphen

0.0

B;B

Vest4

0.046

MutPred

0.20

Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);

MVP

0.014

MPC

1.2

ClinPred

0.051

GERP RS

-0.84

Varity_R

0.029

gMVP

0.096

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over