15-89665767-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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 (★). Synonymous variant affecting the same amino acid position (i.e. P462P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.260

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 -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 GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLIN1	NM_002666.5	c.1385C>T	p.Pro462Leu	missense_variant	9/9	ENST00000300055.10
PLIN1	NM_001145311.2	c.1385C>T	p.Pro462Leu	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLIN1	ENST00000300055.10	c.1385C>T	p.Pro462Leu	missense_variant	9/9	1	NM_002666.5	P1
PLIN1	ENST00000430628.2	c.1385C>T	p.Pro462Leu	missense_variant	9/9	5		P1
PLIN1	ENST00000560330.1	c.124-826C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 31 AN: 150794 Hom.: 0 Cov.: 32

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: 1 AN: 2378 Hom.: 0 AF XY: 0.000628 AC XY: 1 AN XY: 1592

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.: 1 Cov.: 31 AF XY: 0.000336 AC XY: 182 AN XY: 541366

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: 31 AN: 150904 Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 15 AN XY: 73744

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.: 0

Bravo AF: 0.000128

ExAC AF: 0.000318 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
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	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.74	T
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	T
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

Other links and lift over

dbSNP: rs536462615; hg19: chr15-90208998;