19-4847813-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005817.5(PLIN3):c.712C>T(p.Arg238Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,613,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: PLIN3 NM_005817.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLIN3	NM_005817.5	c.712C>T	p.Arg238Cys	missense_variant	6/8	ENST00000221957.9
PLIN3	NM_001164189.2	c.712C>T	p.Arg238Cys	missense_variant	6/8
PLIN3	NM_001164194.2	c.676C>T	p.Arg226Cys	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLIN3	ENST00000221957.9	c.712C>T	p.Arg238Cys	missense_variant	6/8	1	NM_005817.5	P3
PLIN3	ENST00000585479.5	c.712C>T	p.Arg238Cys	missense_variant	6/8	1		A1
PLIN3	ENST00000592528.5	c.676C>T	p.Arg226Cys	missense_variant	6/8	2
PLIN3	ENST00000589163.5	c.407+4C>T		splice_donor_region_variant, intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000156 AC: 39 AN: 250230 Hom.: 1 AF XY: 0.000199 AC XY: 27 AN XY: 135520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1461568 Hom.: 1 Cov.: 50 AF XY: 0.000197 AC XY: 143 AN XY: 727094

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000382

EpiControl AF: 0.000533

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

Dec 05, 2022

The c.712C>T (p.R238C) alteration is located in exon 6 (coding exon 5) of the PLIN3 gene. This alteration results from a C to T substitution at nucleotide position 712, causing the arginine (R) at amino acid position 238 to be replaced by a cysteine (C). 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	Uncertain	0.34
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.7	H;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.8	D;.;.
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.47	P;.;B
Vest4		0.94
MVP		0.36
MPC		0.38
ClinPred		0.98	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.62
gMVP		0.66

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: rs146789635; hg19: chr19-4847825;