Genetic Variant NM_002666.5:c.1507C>A (chr15-89665645-G-T) – 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.1507C>A(p.Pro503Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000739 in 1,353,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P503S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

PLIN1
NM_002666.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.40

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=0.3943096).

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.1507C>A	p.Pro503Thr	missense	Exon 9 of 9	NP_002657.3	O60240
	PLIN1	NM_001145311.2		c.1507C>A	p.Pro503Thr	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.1507C>A	p.Pro503Thr	missense	Exon 9 of 9	ENSP00000300055.5	O60240
PLIN1	ENST00000896664.1		c.1615C>A	p.Pro539Thr	missense	Exon 9 of 9	ENSP00000566723.1
PLIN1	ENST00000896666.1		c.1537C>A	p.Pro513Thr	missense	Exon 9 of 9	ENSP00000566725.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.39e-7

AC:

AN:

1353284

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

667254

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28422

American (AMR)

AF:

0.00

AC:

AN:

32982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24314

East Asian (EAS)

AF:

0.00

AC:

AN:

32062

South Asian (SAS)

AF:

0.00

AC:

AN:

76014

European-Finnish (FIN)

AF:

0.0000264

AC:

AN:

37820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4004

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1061640

Other (OTH)

AF:

0.00

AC:

AN:

56026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.72

M_CAP

Benign

0.044

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.1

PhyloP100

2.4

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.2

REVEL

Benign

0.15

Sift

Benign

0.033

Sift4G

Uncertain

0.055

Polyphen

1.0

Vest4

0.42

MutPred

0.30

Gain of phosphorylation at P503 (P = 0.0354)

MVP

0.34

MPC

2.5

ClinPred

0.95

GERP RS

5.2

Varity_R

0.20

gMVP

0.24

Mutation Taster

=75/25

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over