19-4847696-T-C

Variant summary

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

The NM_005817.5(PLIN3):c.829A>G(p.Ser277Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,597,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PLIN3 NM_005817.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.955

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.211804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLIN3	NM_005817.5	c.829A>G	p.Ser277Gly	missense_variant	6/8	ENST00000221957.9
PLIN3	NM_001164189.2	c.829A>G	p.Ser277Gly	missense_variant	6/8
PLIN3	NM_001164194.2	c.793A>G	p.Ser265Gly	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLIN3	ENST00000221957.9	c.829A>G	p.Ser277Gly	missense_variant	6/8	1	NM_005817.5	P3
PLIN3	ENST00000585479.5	c.829A>G	p.Ser277Gly	missense_variant	6/8	1		A1
PLIN3	ENST00000592528.5	c.793A>G	p.Ser265Gly	missense_variant	6/8	2
PLIN3	ENST00000589163.5	c.407+121A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000444 AC: 1 AN: 225162 Hom.: 0 AF XY: 0.00000818 AC XY: 1 AN XY: 122288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1445702 Hom.: 0 Cov.: 29 AF XY: 0.0000167 AC XY: 12 AN XY: 718194

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: 0.0000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

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

Jun 02, 2023

The c.829A>G (p.S277G) alteration is located in exon 6 (coding exon 5) of the PLIN3 gene. This alteration results from a A to G substitution at nucleotide position 829, causing the serine (S) at amino acid position 277 to be replaced by a glycine (G). 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	0.079
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.070	T;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N;.;.
REVEL	Benign	0.051
Sift	Benign	0.37	T;.;.
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.13
MutPred		0.36		Loss of disorder (P = 0.0972);.;Loss of disorder (P = 0.0972);
MVP		0.11
MPC		0.091
ClinPred		0.051	T
GERP RS		0.70
Varity_R		0.031
gMVP		0.044

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs777147524; hg19: chr19-4847708;