chr12-120322279-C-A

Variant names:

• chr12-120322279-C-A
• rs375742049
• NM_000928.3:c.361G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000928.3(PLA2G1B):​c.361G>T​(p.Asp121Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PLA2G1B NM_000928.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79

Genes affected

PLA2G1B (HGNC:9030): (phospholipase A2 group IB) This gene encodes a secreted member of the phospholipase A2 (PLA2) class of enzymes, which is produced by the pancreatic acinar cells. The encoded calcium-dependent enzyme catalyzes the hydrolysis of the sn-2 position of membrane glycerophospholipids to release arachidonic acid (AA) and lysophospholipids. AA is subsequently converted by downstream metabolic enzymes to several bioactive lipophilic compounds (eicosanoids), including prostaglandins (PGs) and leukotrienes (LTs). The enzyme may be involved in several physiological processes including cell contraction, cell proliferation and pathological response. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a active_site (size 0) in uniprot entity PA21B_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G1B	NM_000928.3	c.361G>T	p.Asp121Tyr	missense_variant	Exon 4 of 4	ENST00000308366.9	NP_000919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G1B	ENST00000308366.9	c.361G>T	p.Asp121Tyr	missense_variant	Exon 4 of 4	1	NM_000928.3	ENSP00000312286.4
PLA2G1B	ENST00000423423	c.*20G>T		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000413594.3
PLA2G1B	ENST00000549767.1	c.274G>T	p.Asp92Tyr	missense_variant	Exon 3 of 3	2		ENSP00000447233.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461776 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727192

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.361G>T (p.D121Y) alteration is located in exon 4 (coding exon 4) of the PLA2G1B gene. This alteration results from a G to T substitution at nucleotide position 361, causing the aspartic acid (D) at amino acid position 121 to be replaced by a tyrosine (Y). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	4.9	H;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-8.5	D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.77		Gain of catalytic residue at N119 (P = 0.0054);.;
MVP		0.75
MPC		0.42
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.97

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: rs375742049; hg19: chr12-120760082;