19-4504576-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001367868.2(PLIN4):​c.3999C>G​(p.Ser1333Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,601,222 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1333N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PLIN4
NM_001367868.2 missense

Scores

3
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Publications

0 publications found
Variant links:
Genes affected
PLIN4 (HGNC:29393): (perilipin 4) Members of the perilipin family, such as PLIN4, coat intracellular lipid storage droplets (Wolins et al., 2003 [PubMed 12840023]).[supplied by OMIM, Feb 2010]
PLIN4 Gene-Disease associations (from GenCC):
  • vacuolar Neuromyopathy
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23412481).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLIN4NM_001367868.2 linkc.3999C>G p.Ser1333Arg missense_variant Exon 8 of 8 ENST00000301286.5 NP_001354797.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLIN4ENST00000301286.5 linkc.3999C>G p.Ser1333Arg missense_variant Exon 8 of 8 5 NM_001367868.2 ENSP00000301286.4 Q96Q06
PLIN4ENST00000633942.1 linkc.4002C>G p.Ser1334Arg missense_variant Exon 8 of 8 5 ENSP00000488481.1 A0A0J9YXN7

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000137
AC:
3
AN:
218594
AF XY:
0.00000824
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000918
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1448990
Hom.:
0
Cov.:
31
AF XY:
0.00000139
AC XY:
1
AN XY:
720472
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33236
American (AMR)
AF:
0.0000687
AC:
3
AN:
43694
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25848
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39102
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84938
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47790
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5734
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1108718
Other (OTH)
AF:
0.00
AC:
0
AN:
59930
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74378
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41462
American (AMR)
AF:
0.0000654
AC:
1
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.00000836
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 10, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3957C>G (p.S1319R) alteration is located in exon 6 (coding exon 6) of the PLIN4 gene. This alteration results from a C to G substitution at nucleotide position 3957, causing the serine (S) at amino acid position 1319 to be replaced by an arginine (R). 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
Pathogenic
0.60
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.073
T;.
Eigen
Benign
-0.026
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.062
N
LIST_S2
Benign
0.49
T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.23
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
3.0
M;.
PhyloP100
1.6
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-4.1
D;.
REVEL
Benign
0.071
Sift
Uncertain
0.0040
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.27
MutPred
0.43
Loss of glycosylation at S1319 (P = 0.0146);.;
MVP
0.17
ClinPred
0.84
D
GERP RS
1.9
Varity_R
0.38
gMVP
0.59
Mutation Taster
=90/10
polymorphism

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

Other links and lift over

dbSNP: rs779184535; hg19: chr19-4504588; API