Genetic Variant NM_001367868.2:c.3967G>A (chr19-4504608-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001367868.2(PLIN4):c.3967G>A(p.Glu1323Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,604,232 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00085 ( 1 hom. )

Consequence

PLIN4
NM_001367868.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.139

Publications

3 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

PLIN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018102735).

BS2

High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLIN4	NM_001367868.2 link	c.3967G>A	p.Glu1323Lys	missense_variant	Exon 8 of 8	ENST00000301286.5	NP_001354797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLIN4	ENST00000301286.5 link	c.3967G>A	p.Glu1323Lys	missense_variant	Exon 8 of 8	5	NM_001367868.2	ENSP00000301286.4		Q96Q06
PLIN4	ENST00000633942.1 link	c.3970G>A	p.Glu1324Lys	missense_variant	Exon 8 of 8	5		ENSP00000488481.1		A0A0J9YXN7

Frequencies

GnomAD3 genomes

AF:

0.000420

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000535

AC:

122

AN:

227846

AF XY:

0.000548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000658

Gnomad ASJ exome

AF:

0.000316

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000118

Gnomad NFE exome

AF:

0.000867

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.000855

AC:

1241

AN:

1452008

Hom.:

Cov.:

AF XY:

0.000834

AC XY:

602

AN XY:

722208

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33364

American (AMR)

AF:

0.000657

AC:

AN:

44146

Ashkenazi Jewish (ASJ)

AF:

0.000424

AC:

AN:

25932

East Asian (EAS)

AF:

0.00

AC:

AN:

39462

South Asian (SAS)

AF:

0.000351

AC:

AN:

85356

European-Finnish (FIN)

AF:

0.0000625

AC:

AN:

47986

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00101

AC:

1119

AN:

1109920

Other (OTH)

AF:

0.000682

AC:

AN:

60088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

157

236

314

393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000420

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41454

American (AMR)

AF:

0.000262

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68034

Other (OTH)

AF:

0.00144

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000733

Hom.:

Bravo

AF:

0.000521

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.000473

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3925G>A (p.E1309K) alteration is located in exon 6 (coding exon 6) of the PLIN4 gene. This alteration results from a G to A substitution at nucleotide position 3925, causing the glutamic acid (E) at amino acid position 1309 to be replaced by a lysine (K). 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

0.080

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.18

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.0075

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.47

T;T

M_CAP

Benign

0.0093

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PhyloP100

-0.14

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.010

Sift

Benign

0.45

T;.

Sift4G

Benign

0.26

T;T

Polyphen

0.0060

B;.

Vest4

0.11

MVP

0.030

ClinPred

0.040

GERP RS

-8.1

Varity_R

0.038

gMVP

0.11

Mutation Taster

=99/1

polymorphism

(source)

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

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NM_001367868.2:c.3967G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over