6-46705200-A-G

Variant names:

• chr6-46705200-A-G
• rs1351406965
• NM_005084.4:c.1142T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005084.4(PLA2G7):​c.1142T>C​(p.Ile381Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,608,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLA2G7 NM_005084.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

Genes affected

PLA2G7 (HGNC:9040): (phospholipase A2 group VII) The protein encoded by this gene is a secreted enzyme that catalyzes the degradation of platelet-activating factor to biologically inactive products. Defects in this gene are a cause of platelet-activating factor acetylhydrolase deficiency. Two transcript variants encoding the same protein have been found for this gene.[provided by RefSeq, Dec 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G7	NM_005084.4	c.1142T>C	p.Ile381Thr	missense_variant	Exon 11 of 12	ENST00000274793.12	NP_005075.3
PLA2G7	NM_001168357.2	c.1142T>C	p.Ile381Thr	missense_variant	Exon 11 of 12		NP_001161829.1
PLA2G7	XM_005249408.5	c.1142T>C	p.Ile381Thr	missense_variant	Exon 11 of 12		XP_005249465.1
PLA2G7	XM_047419359.1	c.1007T>C	p.Ile336Thr	missense_variant	Exon 10 of 11		XP_047275315.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G7	ENST00000274793.12	c.1142T>C	p.Ile381Thr	missense_variant	Exon 11 of 12	1	NM_005084.4	ENSP00000274793.7
PLA2G7	ENST00000537365.1	c.1142T>C	p.Ile381Thr	missense_variant	Exon 11 of 12	1		ENSP00000445666.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456200 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724834

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107136

Other (OTH) AF: 0.00 AC: 0 AN: 60170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

African (AFR) AF: 0.0000724 AC: 3 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1142T>C (p.I381T) alteration is located in exon 11 (coding exon 10) of the PLA2G7 gene. This alteration results from a T to C substitution at nucleotide position 1142, causing the isoleucine (I) at amino acid position 381 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.0	M;M
PhyloP100		8.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.26
Sift	Benign	0.046	D;D
Sift4G	Benign	0.45	T;T
Polyphen		0.31	B;B
Vest4		0.48
MutPred		0.68		Loss of stability (P = 3e-04);Loss of stability (P = 3e-04);
MVP		0.53
MPC		0.019
ClinPred		0.84	D
GERP RS		5.9
Varity_R		0.51
gMVP		0.64
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs1351406965; hg19: chr6-46672937;