NM_003560.4:c.1640A>G

Variant names:

• chr22-38120861-T-C
• rs1060499764
• NM_003560.4:c.1640A>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]

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 rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4	c.1640A>G	p.Glu547Gly	missense_variant	Exon 12 of 17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.1640A>G	p.Glu547Gly	missense_variant	Exon 12 of 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

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;