19-4847701-A-T

Variant names:

• chr19-4847701-A-T
• rs9973235
• NM_005817.5:c.824T>A

Variant summary

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

The NM_005817.5(PLIN3):​c.824T>A​(p.Val275Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,676 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V275A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLIN3 NM_005817.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.46

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLIN3	NM_005817.5	c.824T>A	p.Val275Asp	missense_variant	Exon 6 of 8	ENST00000221957.9	NP_005808.3
PLIN3	NM_001164189.2	c.824T>A	p.Val275Asp	missense_variant	Exon 6 of 8		NP_001157661.1
PLIN3	NM_001164194.2	c.788T>A	p.Val263Asp	missense_variant	Exon 6 of 8		NP_001157666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLIN3	ENST00000221957.9	c.824T>A	p.Val275Asp	missense_variant	Exon 6 of 8	1	NM_005817.5	ENSP00000221957.3
PLIN3	ENST00000585479.5	c.824T>A	p.Val275Asp	missense_variant	Exon 6 of 8	1		ENSP00000465596.1
PLIN3	ENST00000592528.5	c.788T>A	p.Val263Asp	missense_variant	Exon 6 of 8	2		ENSP00000467803.1
PLIN3	ENST00000589163.5	c.405+116T>A		intron_variant	Intron 3 of 4	3		ENSP00000468476.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447676 Hom.: 0 Cov.: 42 AF XY: 0.00000139 AC XY: 1 AN XY: 719264

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.014	B;.;B
Vest4		0.58
MutPred		0.78		Loss of catalytic residue at V275 (P = 0.0026);.;Loss of catalytic residue at V275 (P = 0.0026);
MVP		0.20
MPC		0.20
ClinPred		0.43	T
GERP RS		2.2
Varity_R		0.28
gMVP		0.42

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: rs9973235; hg19: chr19-4847713;