NM_002666.5:c.1248C>T

Variant names:

• chr15-89665904-G-A
• rs8179074
• NM_002666.5:c.1248C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002666.5(PLIN1):​c.1248C>T​(p.Phe416Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,535,726 control chromosomes in the GnomAD database, including 2,198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (180 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2018 hom.)
• Consequence: PLIN1 NM_002666.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.16
• Publications: 2 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: STRONG, SUPPORTIVE, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 15-89665904-G-A is Benign according to our data. Variant chr15-89665904-G-A is described in ClinVar as Benign. ClinVar VariationId is 129972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLIN1	NM_002666.5	c.1248C>T	p.Phe416Phe	synonymous_variant	Exon 9 of 9	ENST00000300055.10	NP_002657.3
PLIN1	NM_001145311.2	c.1248C>T	p.Phe416Phe	synonymous_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.1248C>T	p.Phe416Phe	synonymous_variant	Exon 9 of 9	1	NM_002666.5	ENSP00000300055.5
PLIN1	ENST00000430628.2	c.1248C>T	p.Phe416Phe	synonymous_variant	Exon 9 of 9	5		ENSP00000402167.2
PLIN1	ENST00000560330.1	c.124-963C>T		intron_variant	Intron 2 of 2	5		ENSP00000453426.1

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6077 AN: 152088 Hom.: 180 Cov.: 32

Gnomad AFR AF: 0.00958

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0558

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.0473

GnomAD2 exomes AF: 0.0387 AC: 5975 AN: 154556 AF XY: 0.0394

Gnomad AFR exome AF: 0.00782

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0593

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0495

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0574

GnomAD4 exome AF: 0.0506 AC: 70041 AN: 1383524 Hom.: 2018 Cov.: 31 AF XY: 0.0500 AC XY: 34281 AN XY: 685416

African (AFR) AF: 0.00807 AC: 239 AN: 29630

American (AMR) AF: 0.0316 AC: 1177 AN: 37288

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1543 AN: 24570

East Asian (EAS) AF: 0.000176 AC: 6 AN: 34082

South Asian (SAS) AF: 0.0181 AC: 1422 AN: 78356

European-Finnish (FIN) AF: 0.0566 AC: 1959 AN: 34608

Middle Eastern (MID) AF: 0.0421 AC: 224 AN: 5316

European-Non Finnish (NFE) AF: 0.0561 AC: 60703 AN: 1082174

Other (OTH) AF: 0.0481 AC: 2768 AN: 57500

GnomAD4 genome AF: 0.0399 AC: 6075 AN: 152202 Hom.: 180 Cov.: 32 AF XY: 0.0394 AC XY: 2932 AN XY: 74428

African (AFR) AF: 0.00955 AC: 397 AN: 41570

American (AMR) AF: 0.0348 AC: 533 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 218 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.0151 AC: 73 AN: 4830

European-Finnish (FIN) AF: 0.0558 AC: 591 AN: 10586

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0593 AC: 4032 AN: 67966

Other (OTH) AF: 0.0473 AC: 100 AN: 2114

Alfa AF: 0.0493 Hom.: 48

Bravo AF: 0.0379

Asia WGS AF: 0.00808 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Mar 05, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs8179074; hg19: chr15-90209135; COSMIC: COSV55583479;