19-4504658-C-T

Variant names:

• chr19-4504658-C-T
• rs567197961
• NM_001367868.2:c.3917G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001367868.2(PLIN4):​c.3917G>A​(p.Arg1306Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,602,634 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PLIN4 NM_001367868.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.121555746).
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLIN4	NM_001367868.2	c.3917G>A	p.Arg1306Gln	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	c.3917G>A	p.Arg1306Gln	missense_variant	Exon 8 of 8	5	NM_001367868.2	ENSP00000301286.4
PLIN4	ENST00000633942.1	c.3920G>A	p.Arg1307Gln	missense_variant	Exon 8 of 8	5		ENSP00000488481.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000267 AC: 6 AN: 224956 AF XY: 0.0000321

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000392

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1450292 Hom.: 0 Cov.: 31 AF XY: 0.0000180 AC XY: 13 AN XY: 721448

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.0000226 AC: 1 AN: 44192

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1109982

Other (OTH) AF: 0.0000166 AC: 1 AN: 60072

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000571 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3875G>A (p.R1292Q) 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 3875, causing the arginine (R) at amino acid position 1292 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		1.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Benign	0.033
Sift	Benign	0.15	T;.
Sift4G	Benign	0.18	T;T
Polyphen		0.87	P;.
Vest4		0.31
MutPred		0.38		Loss of catalytic residue at R1292 (P = 0.1049);.;
MVP		0.11
ClinPred		0.92	D
GERP RS		2.3
Varity_R		0.10
gMVP		0.28
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs567197961; hg19: chr19-4504670;