2-28538337-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_153021.5(PLB1):c.574G>A(p.Gly192Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,613,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (1 hom.)
• Consequence: PLB1 NM_153021.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.96

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054699928).
• BP6: Variant 2-28538337-G-A is Benign according to our data. Variant chr2-28538337-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2516853.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLB1	NM_153021.5	c.574G>A	p.Gly192Ser	missense_variant	10/58	ENST00000327757.10
PLB1	NM_001170585.2	c.607G>A	p.Gly203Ser	missense_variant	10/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLB1	ENST00000327757.10	c.574G>A	p.Gly192Ser	missense_variant	10/58	1	NM_153021.5	P1
PLB1	ENST00000422425.6	c.607G>A	p.Gly203Ser	missense_variant	10/57	1
PLB1	ENST00000404858.5	c.604G>A	p.Gly202Ser	missense_variant	10/57	1
PLB1	ENST00000416713.5	c.439G>A	p.Gly147Ser	missense_variant	10/11	5

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000403 AC: 10 AN: 248288 Hom.: 0 AF XY: 0.0000594 AC XY: 8 AN XY: 134660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000554 AC: 81 AN: 1461160 Hom.: 1 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 726896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000674

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74214

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000326 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000297

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.013
Dann	Benign	0.57
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.39	T;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.62	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.040, 0.22	.;B;B
Vest4		0.11, 0.094
MVP		0.061
MPC		0.041
ClinPred		0.034	T
GERP RS		-9.8
Varity_R		0.022
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs149462466; hg19: chr2-28761204; COSMIC: COSV59836488;