rs9973235

Positions:

• chr19-4847701-A-G
• chr19-4847701-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005817.5(PLIN3):​c.824T>C​(p.Val275Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 1,599,220 control chromosomes in the GnomAD database, including 592,895 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.88 (58651 hom., cov: 32)
  • Exomes 𝑓: 0.86 (534244 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7516448E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLIN3	NM_005817.5	c.824T>C	p.Val275Ala	missense_variant	6/8	ENST00000221957.9	NP_005808.3
PLIN3	NM_001164189.2	c.824T>C	p.Val275Ala	missense_variant	6/8		NP_001157661.1
PLIN3	NM_001164194.2	c.788T>C	p.Val263Ala	missense_variant	6/8		NP_001157666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLIN3	ENST00000221957.9	c.824T>C	p.Val275Ala	missense_variant	6/8	1	NM_005817.5	ENSP00000221957.3
PLIN3	ENST00000585479.5	c.824T>C	p.Val275Ala	missense_variant	6/8	1		ENSP00000465596.1
PLIN3	ENST00000592528.5	c.788T>C	p.Val263Ala	missense_variant	6/8	2		ENSP00000467803.1
PLIN3	ENST00000589163.5	c.405+116T>C		intron_variant		3		ENSP00000468476.1

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133433 AN: 152036 Hom.: 58603 Cov.: 32

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.918

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.898

GnomAD3 exomes AF: 0.871 AC: 198297 AN: 227610 Hom.: 86633 AF XY: 0.867 AC XY: 107139 AN XY: 123550

Gnomad AFR exome AF: 0.905

Gnomad AMR exome AF: 0.940

Gnomad ASJ exome AF: 0.859

Gnomad EAS exome AF: 0.907

Gnomad SAS exome AF: 0.848

Gnomad FIN exome AF: 0.857

Gnomad NFE exome AF: 0.849

Gnomad OTH exome AF: 0.875

GnomAD4 exome AF: 0.859 AC: 1242947 AN: 1447066 Hom.: 534244 Cov.: 42 AF XY: 0.859 AC XY: 617528 AN XY: 718910

Gnomad4 AFR exome AF: 0.907

Gnomad4 AMR exome AF: 0.937

Gnomad4 ASJ exome AF: 0.863

Gnomad4 EAS exome AF: 0.876

Gnomad4 SAS exome AF: 0.856

Gnomad4 FIN exome AF: 0.861

Gnomad4 NFE exome AF: 0.853

Gnomad4 OTH exome AF: 0.871

GnomAD4 genome AF: 0.878 AC: 133537 AN: 152154 Hom.: 58651 Cov.: 32 AF XY: 0.880 AC XY: 65426 AN XY: 74382

Gnomad4 AFR AF: 0.906

Gnomad4 AMR AF: 0.918

Gnomad4 ASJ AF: 0.858

Gnomad4 EAS AF: 0.900

Gnomad4 SAS AF: 0.866

Gnomad4 FIN AF: 0.864

Gnomad4 NFE AF: 0.855

Gnomad4 OTH AF: 0.894

Alfa AF: 0.864 Hom.: 138672

Bravo AF: 0.885

TwinsUK AF: 0.852 AC: 3159

ALSPAC AF: 0.847 AC: 3264

ESP6500AA AF: 0.914 AC: 4014

ESP6500EA AF: 0.853 AC: 7331

ExAC AF: 0.863 AC: 104325

Asia WGS AF: 0.852 AC: 2964 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.051	T;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.15	T;T;T
MetaRNN	Benign	0.0000018	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N;.;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.22	N;.;.
REVEL	Benign	0.13
Sift	Benign	0.51	T;.;.
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.031
MPC		0.12
ClinPred		0.0065	T
GERP RS		2.2
Varity_R		0.015
gMVP		0.081

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;