15-41840593-C-T

Position:

• chr15-41840593-C-T

Variant summary

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

The NM_001114633.2(PLA2G4B):​c.152C>T​(p.Thr51Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: PLA2G4B NM_001114633.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

Genes affected

PLA2G4B (HGNC:9036): (phospholipase A2 group IVB) This gene encodes a member of the cytosolic phospholipase A2 protein family. Phospholipase A2 enzymes hydrolyze the sn-2 bond of phospholipids, releasing lysophospholipids and fatty acids. This enzyme may be associated with mitochondria and early endosomes. Most tissues also express read-through transcripts from the upstream gene into this gene, some of which may encode fusion proteins combining the N-terminus of the upstream gene including its JmjC domain with the almost complete coding region of this gene, including the C2 and cytoplasmic phospholipase A2 domains. [provided by RefSeq, Jul 2008]

JMJD7-PLA2G4B (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061046273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G4B	NM_001114633.2	c.152C>T	p.Thr51Met	missense_variant	3/20	ENST00000458483.4
JMJD7-PLA2G4B	NM_005090.4	c.845C>T	p.Thr282Met	missense_variant	8/25
JMJD7-PLA2G4B	NM_001198588.2	c.845C>T	p.Thr282Met	missense_variant	8/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G4B	ENST00000458483.4	c.152C>T	p.Thr51Met	missense_variant	3/20	2	NM_001114633.2	P1
PLA2G4B	ENST00000452633.5	c.152C>T	p.Thr51Met	missense_variant	4/21	5		P1
PLA2G4B	ENST00000461382.5	n.253C>T		non_coding_transcript_exon_variant	3/10	2

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000547 AC: 136 AN: 248558 Hom.: 0 AF XY: 0.000528 AC XY: 71 AN XY: 134574

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000631

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000340 AC: 497 AN: 1461690 Hom.: 0 Cov.: 32 AF XY: 0.000342 AC XY: 249 AN XY: 727122

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000279

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74462

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000413 Hom.: 0

Bravo AF: 0.000487

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2023

The c.845C>T (p.T282M) alteration is located in exon 8 (coding exon 8) of the JMJD7-PLA2G4B gene. This alteration results from a C to T substitution at nucleotide position 845, causing the threonine (T) at amino acid position 282 to be replaced by a methionine (M). 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	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.70	T;T;.;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	0.88	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.062	T;T;D;D
Sift4G	Benign	0.068	T;T;D;D
Polyphen		0.93	.;.;P;P
Vest4		0.44
MVP		0.65
MPC		0.10
ClinPred		0.13	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.55

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: rs146319460; hg19: chr15-42132791;