22-38123251-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_003560.4(PLA2G6):​c.1435C>G​(p.His479Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,406,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

6
13

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.17
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-38123251-G-C is Pathogenic according to our data. Variant chr22-38123251-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 529507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.24451718). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLA2G6NM_003560.4 linkc.1435C>G p.His479Asp missense_variant Exon 11 of 17 ENST00000332509.8 NP_003551.2 O60733-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLA2G6ENST00000332509.8 linkc.1435C>G p.His479Asp missense_variant Exon 11 of 17 1 NM_003560.4 ENSP00000333142.3 O60733-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000213
AC:
3
AN:
1406660
Hom.:
0
Cov.:
32
AF XY:
0.00000288
AC XY:
2
AN XY:
694464
show subpopulations
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:
0.00000185
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000301
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Infantile neuroaxonal dystrophy Pathogenic:2
May 22, 2022
3billion
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.12; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PLA2G6- related disorder (ClinVar ID: VCV000529507 / PMID: 30340910). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 30340910). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 479 of the PLA2G6 protein (p.His479Asp). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 30340910; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 529507). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1
Dec 09, 2023
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30340910, 36233161, 30713958) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Benign
-0.014
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T;.;.
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.91
D;D;.
M_CAP
Benign
0.036
D
MetaRNN
Benign
0.24
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
2.0
M;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Benign
0.12
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.012
D;D;D
Polyphen
0.0020
B;B;B
Vest4
0.43
MVP
0.73
MPC
0.35
ClinPred
0.75
D
GERP RS
2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.54
gMVP
0.80

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1235695530; hg19: chr22-38519258; API