2-28538331-G-A

Variant names:

• chr2-28538331-G-A
• rs1246885515
• NM_153021.5:c.568G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153021.5(PLB1):​c.568G>A​(p.Ala190Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A190V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLB1 NM_153021.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.227
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05968669).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153021.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLB1	NM_153021.5	MANE Select	c.568G>A	p.Ala190Thr	missense	Exon 10 of 58	NP_694566.4
	PLB1	NM_001170585.2		c.601G>A	p.Ala201Thr	missense	Exon 10 of 57	NP_001164056.1	Q6P1J6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLB1	ENST00000327757.10	TSL:1 MANE Select	c.568G>A	p.Ala190Thr	missense	Exon 10 of 58	ENSP00000330442.5	Q6P1J6-1
	PLB1	ENST00000422425.6	TSL:1	c.601G>A	p.Ala201Thr	missense	Exon 10 of 57	ENSP00000416440.2	Q6P1J6-3
	PLB1	ENST00000404858.5	TSL:1	c.595G>A	p.Ala199Thr	missense	Exon 10 of 57	ENSP00000384187.1	H7BYX7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461444 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727032

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.36
DANN	Benign	0.95
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.24	N
PhyloP100		-0.23
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.020
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.080
MutPred		0.38		Gain of loop (P = 0.069)
MVP		0.085
MPC		0.041
ClinPred		0.32	T
GERP RS		-0.33
Varity_R		0.035
gMVP		0.054
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1246885515; hg19: chr2-28761198;