15-89665943-C-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3_Moderate PP5

The NM_002666.5(PLIN1):c.1210-1G>T variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLIN1 NM_002666.5 splice_acceptor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.60

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-89665943-C-A is Pathogenic according to our data. Variant chr15-89665943-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 29827.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLIN1	NM_002666.5	c.1210-1G>T		splice_acceptor_variant		ENST00000300055.10
PLIN1	NM_001145311.2	c.1210-1G>T		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLIN1	ENST00000300055.10	c.1210-1G>T		splice_acceptor_variant		1	NM_002666.5	P1
PLIN1	ENST00000430628.2	c.1210-1G>T		splice_acceptor_variant		5		P1
PLIN1	ENST00000560330.1	c.124-1002G>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1348882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 667482

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

PLIN1-related familial partial lipodystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 24, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: -9
DS_AL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1567075176; hg19: chr15-90209174;