19-4847890-G-A

Variant summary

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

The NM_005817.5(PLIN3):c.635C>T(p.Ala212Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: PLIN3 NM_005817.5 missense, splice_region
• Scores: Splicing: ADA: 0.004639
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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=0.18412784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLIN3	NM_005817.5	c.635C>T	p.Ala212Val	missense_variant, splice_region_variant	6/8	ENST00000221957.9
PLIN3	NM_001164189.2	c.635C>T	p.Ala212Val	missense_variant, splice_region_variant	6/8
PLIN3	NM_001164194.2	c.599C>T	p.Ala200Val	missense_variant, splice_region_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLIN3	ENST00000221957.9	c.635C>T	p.Ala212Val	missense_variant, splice_region_variant	6/8	1	NM_005817.5	P3
PLIN3	ENST00000585479.5	c.635C>T	p.Ala212Val	missense_variant, splice_region_variant	6/8	1		A1
PLIN3	ENST00000592528.5	c.599C>T	p.Ala200Val	missense_variant, splice_region_variant	6/8	2
PLIN3	ENST00000589163.5	c.335C>T	p.Ala112Val	missense_variant, splice_region_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459794 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 726144

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: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 06, 2023

The c.635C>T (p.A212V) 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 635, causing the alanine (A) at amino acid position 212 to be replaced by a valine (V). 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	0.21
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;M
MutationTaster	Benign	0.70	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	D;.;.
REVEL	Benign	0.079
Sift	Benign	0.062	T;.;.
Sift4G	Benign	0.069	T;T;T
Polyphen		0.13	B;.;B
Vest4		0.11
MutPred		0.65		Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);
MVP		0.12
MPC		0.15
ClinPred		0.30	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0046
dbscSNV1_RF	Benign	0.072
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: chr19-4847902;