rs7250947

Variant names:

• chr19-4510518-G-A
• rs7250947
• NM_001367868.2:c.3442C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001367868.2(PLIN4):​c.3442C>T​(p.Arg1148Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0821 in 1,480,548 control chromosomes in the GnomAD database, including 5,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R1148H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.091 (711 hom., cov: 33)
  • Exomes 𝑓: 0.081 (4823 hom.)
• Consequence: PLIN4 NM_001367868.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 14 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002263546).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLIN4	NM_001367868.2	c.3442C>T	p.Arg1148Cys	missense_variant	Exon 5 of 8	ENST00000301286.5	NP_001354797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLIN4	ENST00000301286.5	c.3442C>T	p.Arg1148Cys	missense_variant	Exon 5 of 8	5	NM_001367868.2	ENSP00000301286.4
PLIN4	ENST00000633942.1	c.3445C>T	p.Arg1149Cys	missense_variant	Exon 5 of 8	5		ENSP00000488481.1

Frequencies

GnomAD3 genomes AF: 0.0907 AC: 13798 AN: 152160 Hom.: 710 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0897

Gnomad ASJ AF: 0.0997

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0880

Gnomad OTH AF: 0.0958

GnomAD2 exomes AF: 0.0685 AC: 11074 AN: 161756 AF XY: 0.0672

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.0485

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.000289

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0870

Gnomad OTH exome AF: 0.0750

GnomAD4 exome AF: 0.0811 AC: 107726 AN: 1328270 Hom.: 4823 Cov.: 36 AF XY: 0.0795 AC XY: 51443 AN XY: 647408

African (AFR) AF: 0.130 AC: 3841 AN: 29520

American (AMR) AF: 0.0563 AC: 1405 AN: 24940

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 1927 AN: 19148

East Asian (EAS) AF: 0.000162 AC: 6 AN: 37126

South Asian (SAS) AF: 0.0173 AC: 1082 AN: 62396

European-Finnish (FIN) AF: 0.0473 AC: 2305 AN: 48704

Middle Eastern (MID) AF: 0.0759 AC: 393 AN: 5180

European-Non Finnish (NFE) AF: 0.0883 AC: 92479 AN: 1046878

Other (OTH) AF: 0.0789 AC: 4288 AN: 54378

GnomAD4 genome AF: 0.0907 AC: 13806 AN: 152278 Hom.: 711 Cov.: 33 AF XY: 0.0863 AC XY: 6428 AN XY: 74456

African (AFR) AF: 0.126 AC: 5241 AN: 41552

American (AMR) AF: 0.0895 AC: 1370 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0997 AC: 346 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5184

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4826

European-Finnish (FIN) AF: 0.0452 AC: 480 AN: 10612

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0881 AC: 5989 AN: 68012

Other (OTH) AF: 0.0953 AC: 201 AN: 2110

Alfa AF: 0.0873 Hom.: 1549

Bravo AF: 0.0973

TwinsUK AF: 0.0976 AC: 362

ALSPAC AF: 0.0861 AC: 332

ESP6500AA AF: 0.116 AC: 485

ESP6500EA AF: 0.0822 AC: 692

ExAC AF: 0.0652 AC: 7685

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.94
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.51	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;.
PhyloP100		-1.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.11
Sift	Benign	0.070	T;.
Sift4G	Benign	0.19	T;T
Polyphen		0.96	D;.
Vest4		0.14
ClinPred		0.048	T
GERP RS		-7.8
Varity_R		0.046
gMVP		0.13
Mutation Taster		=98/2	polymorphism (auto)

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: rs7250947; hg19: chr19-4510530; COSMIC: COSV56689924;