19-4839505-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005817.5(PLIN3):c.992G>A(p.Arg331Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 1,386,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 31)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: PLIN3 NM_005817.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.756

Genes affected

PLIN3 (HGNC:16893): (perilipin 3) Mannose 6-phophate receptors (MPRs) deliver lysosomal hydrolase from the Golgi to endosomes and then return to the Golgi complex. The protein encoded by this gene interacts with the cytoplasmic domains of both cation-independent and cation-dependent MPRs, and is required for endosome-to-Golgi transport. This protein also binds directly to the GTPase RAB9 (RAB9A), a member of the RAS oncogene family. The interaction with RAB9 has been shown to increase the affinity of this protein for its cargo. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32146254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLIN3	NM_005817.5	c.992G>A	p.Arg331Gln	missense_variant	8/8	ENST00000221957.9
PLIN3	NM_001164189.2	c.989G>A	p.Arg330Gln	missense_variant	8/8
PLIN3	NM_001164194.2	c.956G>A	p.Arg319Gln	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLIN3	ENST00000221957.9	c.992G>A	p.Arg331Gln	missense_variant	8/8	1	NM_005817.5	P3
PLIN3	ENST00000585479.5	c.989G>A	p.Arg330Gln	missense_variant	8/8	1		A1
PLIN3	ENST00000592528.5	c.956G>A	p.Arg319Gln	missense_variant	8/8	2
PLIN3	ENST00000589163.5	c.566G>A	p.Arg189Gln	missense_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000203 AC: 4 AN: 197282 Hom.: 0 AF XY: 0.0000191 AC XY: 2 AN XY: 104902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000586

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000218

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000937 AC: 13 AN: 1386952 Hom.: 0 Cov.: 31 AF XY: 0.0000118 AC XY: 8 AN XY: 680150

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.0000277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000263

Gnomad4 FIN exome AF: 0.0000198

Gnomad4 NFE exome AF: 0.00000654

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ExAC AF: 0.0000250 AC: 3

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

Nov 29, 2021

The c.992G>A (p.R331Q) alteration is located in exon 8 (coding exon 7) of the PLIN3 gene. This alteration results from a G to A substitution at nucleotide position 992, causing the arginine (R) at amino acid position 331 to be replaced by a glutamine (Q). 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	0.078
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	0.78	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N;.;.
REVEL	Benign	0.13
Sift	Benign	0.17	T;.;.
Sift4G	Benign	0.19	T;T;T
Polyphen		0.94	P;.;P
Vest4		0.19
MutPred		0.76		Loss of MoRF binding (P = 0.0364);.;.;
MVP		0.23
MPC		0.20
ClinPred		0.29	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs775451246; hg19: chr19-4839517;