19-4839293-C-T

Position:

• chr19-4839293-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.1204G>A​(p.Asp402Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PLIN3 NM_005817.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76

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=0.40546563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLIN3	NM_005817.5	c.1204G>A	p.Asp402Asn	missense_variant	8/8	ENST00000221957.9	NP_005808.3
PLIN3	NM_001164189.2	c.1201G>A	p.Asp401Asn	missense_variant	8/8		NP_001157661.1
PLIN3	NM_001164194.2	c.1168G>A	p.Asp390Asn	missense_variant	8/8		NP_001157666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLIN3	ENST00000221957.9	c.1204G>A	p.Asp402Asn	missense_variant	8/8	1	NM_005817.5	ENSP00000221957.3
PLIN3	ENST00000585479.5	c.1201G>A	p.Asp401Asn	missense_variant	8/8	1		ENSP00000465596.1
PLIN3	ENST00000592528.5	c.1168G>A	p.Asp390Asn	missense_variant	8/8	2		ENSP00000467803.1
PLIN3	ENST00000589163.5	c.775G>A	p.Asp259Asn	missense_variant	5/5	3		ENSP00000468476.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727192

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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.1204G>A (p.D402N) 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 1204, causing the aspartic acid (D) at amino acid position 402 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.6	H;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.2	D;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.49	P;.;B
Vest4		0.20
MutPred		0.68		Loss of stability (P = 0.1452);.;.;
MVP		0.14
MPC		0.21
ClinPred		0.96	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.47

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: rs2093625235; hg19: chr19-4839305;