rs1060499764

Positions:

• chr22-38120861-T-C
• chr22-38120861-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_003560.4(PLA2G6):​c.1640A>G​(p.Glu547Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.53

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]

PLA2G6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain PNPLA (size 184) in uniprot entity PLPL9_HUMAN there are 36 pathogenic changes around while only 3 benign (92%) in NM_003560.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-38120861-T-C is Pathogenic according to our data. Variant chr22-38120861-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38120861-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4	c.1640A>G	p.Glu547Gly	missense_variant	12/17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.1640A>G	p.Glu547Gly	missense_variant	12/17	1	NM_003560.4	ENSP00000333142.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile neuroaxonal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PLA2G6 related disorder (ClinVar ID: VCV000402192, PS1_P). 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: 26539891, PM3_M). The variant was co-segregated with Infantile neuroaxonal dystrophy 1 in multiple affected family members (PMID: 26539891, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.867, PP3_P). A missense variant is a common mechanism associated with Infantile neuroaxonal dystrophy 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 05, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.025	B;D;D
Vest4		0.57
MutPred		0.49		Gain of helix (P = 0.0225);.;.;
MVP		0.84
MPC		0.37
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.30
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060499764; hg19: chr22-38516868;