15-89665866-C-G

Position:

• chr15-89665866-C-G

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.1286G>C​(p.Arg429Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000518 in 1,352,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.415

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=0.07931328).
• BS2: High AC in GnomAdExome4 at 7 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/exons	MANE	Protein	UniProt
PLIN1	NM_002666.5	c.1286G>C	p.Arg429Pro	missense_variant	9/9	ENST00000300055.10	NP_002657.3
PLIN1	NM_001145311.2	c.1286G>C	p.Arg429Pro	missense_variant	9/9		NP_001138783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLIN1	ENST00000300055.10	c.1286G>C	p.Arg429Pro	missense_variant	9/9	1	NM_002666.5	ENSP00000300055.5
PLIN1	ENST00000430628.2	c.1286G>C	p.Arg429Pro	missense_variant	9/9	5		ENSP00000402167.2
PLIN1	ENST00000560330.1	c.124-925G>C		intron_variant		5		ENSP00000453426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000518 AC: 7 AN: 1352092 Hom.: 0 Cov.: 31 AF XY: 0.00000450 AC XY: 3 AN XY: 667324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000657

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Mar 21, 2023

The c.1286G>C (p.R429P) alteration is located in exon 9 (coding exon 8) of the PLIN1 gene. This alteration results from a G to C substitution at nucleotide position 1286, causing the arginine (R) at amino acid position 429 to be replaced by a proline (P). 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	0.075
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.4
DANN	Benign	0.66
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.42	.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.035
Sift	Benign	0.22	T;T
Sift4G	Benign	0.097	T;T
Polyphen		0.47	P;P
Vest4		0.072
MutPred		0.23		Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);
MVP		0.030
MPC		1.6
ClinPred		0.49	T
GERP RS		-5.0
Varity_R		0.13
gMVP		0.14

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: rs779519972; hg19: chr15-90209097;