rs150190277

Positions:

• chr22-38143219-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003560.4(PLA2G6):​c.495G>C​(p.Gly165=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,614,166 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G165G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (3 hom.)
• Consequence: PLA2G6 NM_003560.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0300

Genes affected

PLA2G6 (HGNC:9039): (phospholipase A2 group VI) The protein encoded by this gene is an A2 phospholipase, a class of enzyme that catalyzes the release of fatty acids from phospholipids. The encoded protein may play a role in phospholipid remodelling, arachidonic acid release, leukotriene and prostaglandin synthesis, fas-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells. Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only three of them have been determined to date. [provided by RefSeq, Dec 2010]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 22-38143219-C-G is Benign according to our data. Variant chr22-38143219-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159771.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chr22-38143219-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00355 (540/152304) while in subpopulation AFR AF= 0.012 (500/41554). AF 95% confidence interval is 0.0112. There are 3 homozygotes in gnomad4. There are 244 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4	c.495G>C	p.Gly165=	synonymous_variant	4/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8	c.495G>C	p.Gly165=	synonymous_variant	4/17	1	NM_003560.4	P3
	ENST00000624072.1	n.13004C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152186 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.000191

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000927 AC: 233 AN: 251466 Hom.: 1 AF XY: 0.000677 AC XY: 92 AN XY: 135914

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000428 AC: 625 AN: 1461862 Hom.: 3 Cov.: 33 AF XY: 0.000371 AC XY: 270 AN XY: 727234

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152304 Hom.: 3 Cov.: 32 AF XY: 0.00328 AC XY: 244 AN XY: 74476

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000962 Hom.: 0

Bravo AF: 0.00392

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PLA2G6: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2021	- -

Iron accumulation in brain Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Infantile neuroaxonal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.9
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs150190277; hg19: chr22-38539226;