chr15-89665872-T-C

Variant names:

• chr15-89665872-T-C
• rs1003587869
• NM_002666.5:c.1280A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_002666.5(PLIN1):​c.1280A>G​(p.Glu427Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000397 in 1,510,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.625
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08065644).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1280A>G	p.Glu427Gly	missense	Exon 9 of 9	NP_002657.3	O60240
	PLIN1	NM_001145311.2		c.1280A>G	p.Glu427Gly	missense	Exon 9 of 9	NP_001138783.1	O60240

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLIN1	ENST00000300055.10	TSL:1 MANE Select	c.1280A>G	p.Glu427Gly	missense	Exon 9 of 9	ENSP00000300055.5	O60240
	PLIN1	ENST00000896664.1		c.1388A>G	p.Glu463Gly	missense	Exon 9 of 9	ENSP00000566723.1
	PLIN1	ENST00000896666.1		c.1310A>G	p.Glu437Gly	missense	Exon 9 of 9	ENSP00000566725.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.00000368 AC: 5 AN: 1358064 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 670932

African (AFR) AF: 0.00 AC: 0 AN: 28632

American (AMR) AF: 0.00 AC: 0 AN: 33854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24006

East Asian (EAS) AF: 0.0000309 AC: 1 AN: 32324

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4964

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068288

Other (OTH) AF: 0.0000533 AC: 3 AN: 56298

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74234

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67952

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	PLIN1-related familial partial lipodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		0.63
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.034
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.046
MutPred		0.16		Loss of helix (P = 0.0033)
MVP		0.048
MPC		1.5
ClinPred		0.22	T
GERP RS		1.4
Varity_R		0.053
gMVP		0.19
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1003587869; hg19: chr15-90209103;