NM_002666.5:c.1448G>C

Variant names:

• chr15-89665704-C-G
• rs930311706
• NM_002666.5:c.1448G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BS2_Supporting

The NM_002666.5(PLIN1):​c.1448G>C​(p.Gly483Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000379 in 1,318,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G483D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.188
• 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041152894).
• BP6: Variant 15-89665704-C-G is Benign according to our data. Variant chr15-89665704-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2305643.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.1448G>C	p.Gly483Ala	missense	Exon 9 of 9	NP_002657.3	O60240
	PLIN1	NM_001145311.2		c.1448G>C	p.Gly483Ala	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.1448G>C	p.Gly483Ala	missense	Exon 9 of 9	ENSP00000300055.5	O60240
	PLIN1	ENST00000896664.1		c.1556G>C	p.Gly519Ala	missense	Exon 9 of 9	ENSP00000566723.1
	PLIN1	ENST00000896666.1		c.1478G>C	p.Gly493Ala	missense	Exon 9 of 9	ENSP00000566725.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000379 AC: 5 AN: 1318662 Hom.: 0 Cov.: 31 AF XY: 0.00000615 AC XY: 4 AN XY: 650052

African (AFR) AF: 0.00 AC: 0 AN: 26998

American (AMR) AF: 0.00 AC: 0 AN: 28514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23396

East Asian (EAS) AF: 0.000103 AC: 3 AN: 29212

South Asian (SAS) AF: 0.00 AC: 0 AN: 72360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3860

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1046140

Other (OTH) AF: 0.0000367 AC: 2 AN: 54472

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.38
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.19
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.14
Sift	Benign	0.92	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.18		Gain of glycosylation at P480 (P = 0.0805)
MVP		0.014
MPC		1.3
ClinPred		0.059	T
GERP RS		1.7
Varity_R		0.023
gMVP		0.088
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs930311706; hg19: chr15-90208935;