15-89665760-C-A

Position:

• chr15-89665760-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002666.5(PLIN1):​c.1392G>T​(p.Ala464Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,273,274 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (7 hom.)
• Consequence: PLIN1 NM_002666.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.679

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 15-89665760-C-A is Benign according to our data. Variant chr15-89665760-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 710652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89665760-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.679 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (391/150840) while in subpopulation NFE AF= 0.00337 (228/67662). AF 95% confidence interval is 0.00301. There are 1 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 391 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLIN1	NM_002666.5	c.1392G>T	p.Ala464Ala	synonymous_variant	9/9	ENST00000300055.10	NP_002657.3
PLIN1	NM_001145311.2	c.1392G>T	p.Ala464Ala	synonymous_variant	9/9		NP_001138783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLIN1	ENST00000300055.10	c.1392G>T	p.Ala464Ala	synonymous_variant	9/9	1	NM_002666.5	ENSP00000300055.5
PLIN1	ENST00000430628.2	c.1392G>T	p.Ala464Ala	synonymous_variant	9/9	5		ENSP00000402167.2
PLIN1	ENST00000560330.1	c.124-819G>T		intron_variant		5		ENSP00000453426.1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 391 AN: 150732 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000412

Gnomad AMI AF: 0.0177

Gnomad AMR AF: 0.000331

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00387

GnomAD3 exomes AF: 0.0117 AC: 56 AN: 4788 Hom.: 0 AF XY: 0.0110 AC XY: 36 AN XY: 3264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.0472

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.00335 AC: 3756 AN: 1122434 Hom.: 7 Cov.: 31 AF XY: 0.00345 AC XY: 1864 AN XY: 540570

Gnomad4 AFR exome AF: 0.000531

Gnomad4 AMR exome AF: 0.000237

Gnomad4 ASJ exome AF: 0.000140

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00131

Gnomad4 FIN exome AF: 0.0190

Gnomad4 NFE exome AF: 0.00333

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00259 AC: 391 AN: 150840 Hom.: 1 Cov.: 32 AF XY: 0.00279 AC XY: 206 AN XY: 73712

Gnomad4 AFR AF: 0.000411

Gnomad4 AMR AF: 0.000330

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000391

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0111

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.00383

Alfa AF: 0.00202 Hom.: 0

Bravo AF: 0.00173

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PLIN1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2018	- -

PLIN1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 23, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.5
DANN	Benign	0.80

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: rs536062857; hg19: chr15-90208991;