chr15-89665596-C-A

Variant names:

• chr15-89665596-C-A
• rs746427650
• NM_002666.5:c.1556G>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_002666.5(PLIN1):​c.1556G>T​(p.Arg519Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000851 in 1,527,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16650146).
• BS2: High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLIN1	NM_002666.5	c.1556G>T	p.Arg519Leu	missense_variant	Exon 9 of 9	ENST00000300055.10	NP_002657.3
PLIN1	NM_001145311.2	c.1556G>T	p.Arg519Leu	missense_variant	Exon 9 of 9		NP_001138783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLIN1	ENST00000300055.10	c.1556G>T	p.Arg519Leu	missense_variant	Exon 9 of 9	1	NM_002666.5	ENSP00000300055.5
PLIN1	ENST00000430628.2	c.1556G>T	p.Arg519Leu	missense_variant	Exon 9 of 9	5		ENSP00000402167.2
PLIN1	ENST00000560330.1	c.124-655G>T		intron_variant	Intron 2 of 2	5		ENSP00000453426.1

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151556 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000468 AC: 6 AN: 128316 Hom.: 0 AF XY: 0.0000284 AC XY: 2 AN XY: 70510

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.000170

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: 0.0000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000509 AC: 7 AN: 1375446 Hom.: 0 Cov.: 31 AF XY: 0.00000589 AC XY: 4 AN XY: 678820

Gnomad4 AFR exome AF: 0.0000986

Gnomad4 AMR exome AF: 0.0000857

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.34e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000396 AC: 6 AN: 151670 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74118

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1556G>T (p.R519L) alteration is located in exon 9 (coding exon 8) of the PLIN1 gene. This alteration results from a G to T substitution at nucleotide position 1556, causing the arginine (R) at amino acid position 519 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	0.33
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.090
Sift	Benign	0.031	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.48	P;P
Vest4		0.39
MutPred		0.33		Loss of MoRF binding (P = 0.0115);Loss of MoRF binding (P = 0.0115);
MVP		0.23
MPC		1.9
ClinPred		0.053	T
GERP RS		4.1
Varity_R		0.18
gMVP		0.086

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: rs746427650; hg19: chr15-90208827;