2-28525298-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_153021.5(PLB1):c.275A>G(p.Lys92Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,690 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0017 (40 hom.)
• Consequence: PLB1 NM_153021.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21

Genes affected

PLB1 (HGNC:30041): (phospholipase B1) This gene encodes a membrane-associated phospholipase that displays lysophospholipase and phospholipase A2 activities through removal of sn-1 and sn-2 fatty acids of glycerophospholipids. In addition, it displays lipase and retinyl ester hydrolase activities. The encoded protein is highly conserved and is composed of a large, glycosylated extracellular domain composed of four tandem homologous domains, followed by a hydrophobic segment that anchors the enzyme to the membrane and a short C-terminal cytoplasmic tail. This gene has been identified as a candidate rheumatoid arthritis risk gene. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038392842).
• BP6: Variant 2-28525298-A-G is Benign according to our data. Variant chr2-28525298-A-G is described in ClinVar as [Benign]. Clinvar id is 740634.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLB1	NM_153021.5	c.275A>G	p.Lys92Arg	missense_variant	5/58	ENST00000327757.10
PLB1	NM_001170585.2	c.275A>G	p.Lys92Arg	missense_variant	5/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLB1	ENST00000327757.10	c.275A>G	p.Lys92Arg	missense_variant	5/58	1	NM_153021.5	P1
PLB1	ENST00000422425.6	c.275A>G	p.Lys92Arg	missense_variant	5/57	1
PLB1	ENST00000404858.5	c.272A>G	p.Lys91Arg	missense_variant	5/57	1
PLB1	ENST00000416713.5	c.107A>G	p.Lys36Arg	missense_variant	5/11	5

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152182 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00366 AC: 918 AN: 251020 Hom.: 10 AF XY: 0.00321 AC XY: 435 AN XY: 135708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00174 AC: 2550 AN: 1461390 Hom.: 40 Cov.: 31 AF XY: 0.00165 AC XY: 1202 AN XY: 726962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00310

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.000334

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00266 AC: 405 AN: 152300 Hom.: 2 Cov.: 30 AF XY: 0.00384 AC XY: 286 AN XY: 74474

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0295

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000686 Hom.: 1

Bravo AF: 0.000204

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00347 AC: 421

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	12
Dann	Benign	0.94
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.56	T;T;T
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.70, 0.013	.;P;B
Vest4		0.23, 0.20
MVP		0.048
MPC		0.048
ClinPred		0.029	T
GERP RS		2.0
Varity_R		0.064
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs145379829; hg19: chr2-28748165;