19-4523919-C-G

Variant names:

• chr19-4523919-C-G
• rs377657199
• NM_001013706.3:c.1001G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001013706.3(PLIN5):​c.1001G>C​(p.Arg334Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000393 in 1,526,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R334C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: PLIN5 NM_001013706.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.339
• Publications: 1 publications found

Genes affected

PLIN5 (HGNC:33196): (perilipin 5) Predicted to enable identical protein binding activity and lipase binding activity. Predicted to be involved in several processes, including negative regulation of peroxisome proliferator activated receptor signaling pathway; regulation of lipase activity; and regulation of lipid metabolic process. Located in intracellular membrane-bounded organelle and lipid droplet. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3110019).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013706.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLIN5	NM_001013706.3	MANE Select	c.1001G>C	p.Arg334Pro	missense	Exon 8 of 8	NP_001013728.2	Q00G26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLIN5	ENST00000381848.7	TSL:1 MANE Select	c.1001G>C	p.Arg334Pro	missense	Exon 8 of 8	ENSP00000371272.2	Q00G26
	PLIN5	ENST00000905186.1		c.1238G>C	p.Arg413Pro	missense	Exon 9 of 9	ENSP00000575245.1
	PLIN5	ENST00000905182.1		c.1202G>C	p.Arg401Pro	missense	Exon 9 of 9	ENSP00000575241.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 5 AN: 1374702 Hom.: 0 Cov.: 30 AF XY: 0.00000295 AC XY: 2 AN XY: 678964

African (AFR) AF: 0.00 AC: 0 AN: 29364

American (AMR) AF: 0.00 AC: 0 AN: 33950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24414

East Asian (EAS) AF: 0.00 AC: 0 AN: 34534

South Asian (SAS) AF: 0.00 AC: 0 AN: 77888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1077836

Other (OTH) AF: 0.00 AC: 0 AN: 57390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.34
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.19
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Polyphen		0.66	P
Vest4		0.52
MutPred		0.54		Gain of catalytic residue at R334 (P = 0.0173)
MVP		0.28
MPC		0.77
ClinPred		0.55	D
GERP RS		1.7
Varity_R		0.34
gMVP		0.55
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs377657199; hg19: chr19-4523931;