2-28529744-G-T

Variant names:

• chr2-28529744-G-T
• rs147363629
• NM_153021.5:c.433G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153021.5(PLB1):​c.433G>T​(p.Ala145Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,613,972 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 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: PLB1 NM_153021.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.93

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07894778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLB1	NM_153021.5	c.433G>T	p.Ala145Ser	missense_variant	Exon 8 of 58	ENST00000327757.10	NP_694566.4
PLB1	NM_001170585.2	c.433G>T	p.Ala145Ser	missense_variant	Exon 8 of 57		NP_001164056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLB1	ENST00000327757.10	c.433G>T	p.Ala145Ser	missense_variant	Exon 8 of 58	1	NM_153021.5	ENSP00000330442.5
PLB1	ENST00000422425.6	c.433G>T	p.Ala145Ser	missense_variant	Exon 8 of 57	1		ENSP00000416440.2
PLB1	ENST00000404858.5	c.427G>T	p.Ala143Ser	missense_variant	Exon 8 of 57	1		ENSP00000384187.1
PLB1	ENST00000416713.5	c.265G>T	p.Ala89Ser	missense_variant	Exon 8 of 11	5		ENSP00000407076.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251400 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135878

Gnomad AFR exome AF: 0.00111

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461858 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 727234

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74310

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000351

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.433G>T (p.A145S) alteration is located in exon 8 (coding exon 8) of the PLB1 gene. This alteration results from a G to T substitution at nucleotide position 433, causing the alanine (A) at amino acid position 145 to be replaced by a serine (S). 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	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	.;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.079	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.9	.;M;M
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.7	D;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.87, 1.0	.;P;D
Vest4		0.50, 0.56
MVP		0.23
MPC		0.10
ClinPred		0.34	T
GERP RS		5.9
Varity_R		0.13
gMVP		0.43

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: rs147363629; hg19: chr2-28752611;