15-89665896-A-C

Position:

• chr15-89665896-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002666.5(PLIN1):​c.1256T>G​(p.Ile419Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLIN1 NM_002666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17858902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLIN1	NM_002666.5	c.1256T>G	p.Ile419Ser	missense_variant	9/9	ENST00000300055.10	NP_002657.3
PLIN1	NM_001145311.2	c.1256T>G	p.Ile419Ser	missense_variant	9/9		NP_001138783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLIN1	ENST00000300055.10	c.1256T>G	p.Ile419Ser	missense_variant	9/9	1	NM_002666.5	ENSP00000300055.5
PLIN1	ENST00000430628.2	c.1256T>G	p.Ile419Ser	missense_variant	9/9	5		ENSP00000402167.2
PLIN1	ENST00000560330.1	c.124-955T>G		intron_variant		5		ENSP00000453426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.1256T>G (p.I419S) alteration is located in exon 9 (coding exon 8) of the PLIN1 gene. This alteration results from a T to G substitution at nucleotide position 1256, causing the isoleucine (I) at amino acid position 419 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	0.012
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.66	.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.93	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.16	N;N
REVEL	Benign	0.11
Sift	Benign	0.042	D;D
Sift4G	Benign	0.92	T;T
Polyphen		0.42	B;B
Vest4		0.35
MutPred		0.21		Gain of phosphorylation at I419 (P = 0.0053);Gain of phosphorylation at I419 (P = 0.0053);
MVP		0.18
MPC		2.4
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.23
gMVP		0.31

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-90209127;