chr2-28529756-G-T

Position:

• chr2-28529756-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153021.5(PLB1):​c.445G>T​(p.Val149Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00144 in 1,614,106 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (10 hom.)
• Consequence: PLB1 NM_153021.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.45

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005537182).
• BP6: Variant 2-28529756-G-T is Benign according to our data. Variant chr2-28529756-G-T is described in ClinVar as [Benign]. Clinvar id is 767788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00801 (1220/152238) while in subpopulation AFR AF= 0.0281 (1167/41530). AF 95% confidence interval is 0.0268. There are 21 homozygotes in gnomad4. There are 564 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLB1	NM_153021.5	c.445G>T	p.Val149Leu	missense_variant	8/58	ENST00000327757.10
PLB1	NM_001170585.2	c.445G>T	p.Val149Leu	missense_variant	8/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLB1	ENST00000327757.10	c.445G>T	p.Val149Leu	missense_variant	8/58	1	NM_153021.5	P1
PLB1	ENST00000422425.6	c.445G>T	p.Val149Leu	missense_variant	8/57	1
PLB1	ENST00000404858.5	c.442G>T	p.Val148Leu	missense_variant	8/57	1
PLB1	ENST00000416713.5	c.277G>T	p.Val93Leu	missense_variant	8/11	5

Frequencies

GnomAD3 genomes AF: 0.00802 AC: 1220 AN: 152120 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00229 AC: 577 AN: 251418 Hom.: 11 AF XY: 0.00182 AC XY: 247 AN XY: 135882

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000757 AC: 1106 AN: 1461868 Hom.: 10 Cov.: 33 AF XY: 0.000671 AC XY: 488 AN XY: 727240

Gnomad4 AFR exome AF: 0.0262

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00801 AC: 1220 AN: 152238 Hom.: 21 Cov.: 32 AF XY: 0.00758 AC XY: 564 AN XY: 74444

Gnomad4 AFR AF: 0.0281

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00408 Hom.: 2

Bravo AF: 0.00934

ESP6500AA AF: 0.0288 AC: 127

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00287 AC: 349

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	.;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	2.9	.;M;M
MutationTaster	Benign	0.51	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.012	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.40, 1.0	.;B;D
Vest4		0.65, 0.68
MutPred		0.38		.;Gain of ubiquitination at K153 (P = 0.123);Gain of ubiquitination at K153 (P = 0.123);
MVP		0.21
MPC		0.11
ClinPred		0.053	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75175520; hg19: chr2-28752623;